Muscarinic m1 receptor agonists

ABSTRACT

This invention relates to compounds that are agonists of the muscarinic M1 receptor and which are useful in the treatment of muscarinic M1 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds provided are of formula I, where n is 1 or 2; p is 0, 1 or 2; q is 0, 1 or 2; and R1-R6 are as defined herein.

This invention relates to compounds that are agonists of the muscarinicM1 receptor and which are useful in the treatment of muscarinic M1receptor mediated diseases. Also provided are pharmaceuticalcompositions containing the compounds and the therapeutic uses of thecompounds.

BACKGROUND OF THE INVENTION

Muscarinic acetylcholine receptors (mAChRs) are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Five mAChR subtypes have been cloned, M₁ to M₅. The M₁mAChR is predominantly expressed post-synaptically in the cortex,hippocampus, striatum and thalamus; M₂ mAChRs are located predominantlyin the brainstem and thalamus, though also in the cortex, hippocampusand striatum where they reside on cholinergic synaptic terminals(Langmead et alt 2008 Br J Pharmacol). However, M₂ mAChRs are alsoexpressed peripherally on cardiac tissue (where they mediate the vagalinnervation of the heart) and in smooth muscle and exocrine glands. M₃mAChRs are expressed at relatively low level in the CNS but are widelyexpressed in smooth muscle and glandular tissues such as sweat andsalivary glands (Langmead et al., 2008 Br J Pharmacol).

Muscarinic receptors in the central nervous system, especially the M₁mAChR, play a critical role in mediating higher cognitive processing.Diseases associated with cognitive impairments, such as Alzheimer'sdisease, are accompanied by loss of cholinergic neurons in the basalforebrain (Whitehouse et al., 1982 Science). In schizophrenia, whichalso has cognitive impairment as an important component of the clinicalpicture, mAChR density is reduced in the pre-frontal cortex, hippocampusand caudate putamen of schizophrenic subjects (Dean et al., 2002 MolPsychiatry). Furthermore, in animal models, blockade or damage tocentral cholinergic pathways results in profound cognitive deficits andnon-selective mAChR antagonists have been shown to inducepsychotomimetic effects in psychiatric patients. Cholinergic replacementtherapy has largely been based on the use of acetylcholinesteraseinhibitors to prevent the breakdown of endogenous acetylcholine. Thesecompounds have shown efficacy versus symptomatic cognitive decline inthe clinic, but give rise to dose-limiting adverse events resulting fromstimulation of peripheral M₂ and M₃ mAChRs including disturbedgastrointestinal motility, bradycardia, nausea and vomiting(http://www.drugs.com/pro/donepezil.html;http://www.drugs.com/pro/rivastigmine.html).

Further discovery efforts have targeted the identification of direct M₁mAChR agonists with the aim of inducing selective improvements incognitive function with a favourable adverse effect profile. Suchefforts resulted in the identification of a range of agonists,exemplified by compounds such as xanomeline, AF267B, sabcomeline,milameline and cevimeline. Many of these compounds have been shown to behighly effective in pre-clinical models of cognition in both rodentsand/or non-human primates. Milameline has shown efficacy versusscopolamine-induced deficits in working and spatial memory in rodents;sabcomeline displayed efficacy in a visual object discrimination task inmarmosets and xanomeline reversed mAChR antagonist-induced deficits incognitive performance in a passive avoidance paradigm.

Alzheimer's disease (AD) is the most common neurodegenerative disorder(26.6 million people worldwide in 2006) that affects the elderly,resulting in profound memory loss and cognitive dysfunction. Theaetiology of the disease is complex, but is characterised by twohallmark brain pathologies: aggregates of amyloid plaques, largelycomposed of amyloid-β peptide (Aβ), and neurofibrillary tangles, formedby hyperphosphorylated tau proteins. The accumulation of Aβ is thoughtto be the central feature in the progression of AD and, as such, manyputative therapies for the treatment of AD are currently targetinginhibition of Aβ production. Aβ is derived from proteolytic cleavage ofthe membrane bound amyloid precursor protein (APP). APP is processed bytwo routes, nonamyloidgenic and amyloidgenic. Cleavage of APP byγ-secretase is common to both pathways, but in the former APP is cleavedby an α-secretase to yield soluble APPα. However, in the amyloidgenicroute, APP is cleaved by β-secretase to yield soluble APPβ and also Aβ.In vitro studies have shown that mAChR agonists can promote theprocessing of APP toward the soluble, non-amyloidogenic pathway. In vivostudies showed that the mAChR agonist, AF267B, altered disease-likepathology in the 3×TgAD transgenic mouse, a model of the differentcomponents of Alzheimer's disease (Caccamo et al., 2006 Neuron). ThemAChR agonist cevimeline has been shown to give a small, butsignificant, reduction in cerebrospinal fluid levels of Aβ inAlzheimer's patients, thus demonstrating potential disease modifyingefficacy (Nitsch et al., 2000 Neurol).

Preclinical studies have suggested that mAChR agonists display anatypical antipsychotic-like profile in a range of pre-clinicalparadigms. The mAChR agonist, xanomeline, reverses a number of dopaminemediated behaviours, including amphetamine induced locomotion in rats,apomorphine induced climbing in mice, dopamine agonist driven turning inunilateral 6-OH-DA lesioned rats and amphetamine induced motor unrest inmonkeys (without EPS liability) It also has been shown to inhibit A10,but not A9, dopamine cell firing and conditioned avoidance and inducesc-fos expression in prefrontal cortex and nucleus accumbens, but not instriatum in rats. These data are all suggestive of an atypicalantipsychotic-like profile (Mirza et al., 1999 CNS Drug Rev).

Xanomeline, sabcomeline, milameline and cevimeline have all progressedinto various stages of clinical development for the treatment ofAlzheimer's disease and/or schizophrenia. Phase II clinical studies withxanomeline demonstrated its efficacy versus various cognitive symptomdomains, including behavioural disturbances and hallucinationsassociated with Alzheimer's disease (Bodick et al., 1997 Arch Neurol).This compound was also assessed in a small Phase II study ofschizophrenics and gave a significant reduction in positive and negativesymptoms when compared to placebo control (Shekhar et al., 2008 Am JPsych). However, in all clinical studies xanomeline and other relatedmAChR agonists have displayed an unacceptable safety margin with respectto cholinergic adverse events, including nausea, gastrointestinal pain,diahorrhea, diaphoresis (excessive sweating), hypersalivation (excessivesalivation), syncope and bradycardia.

Muscarinic receptors are involved in central and peripheral pain. Paincan be divided into three different types: acute, inflammatory, andneuropathic. Acute pain serves an important protective function inkeeping the organism safe from stimuli that may produce tissue damage;however management of post-surgical pain is required. Inflammatory painmay occur for many reasons including tissue damage, autoimmune response,and pathogen invasion and is triggered by the action of inflammatorymediators such as neuropeptides and prostaglandins which result inneuronal inflammation and pain. Neuropathic pain is associated withabnormal painful sensations to non-painful stimuli. Neuropathic pain isassociated with a number of different diseases/traumas such as spinalcord injury, multiple sclerosis, diabetes (diabetic neuropathy), viralinfection (such as HIV or Herpes). It is also common in cancer both as aresult of the disease or a side effect of chemotherapy. Activation ofmuscarinic receptors has been shown to be analgesic across a number ofpain states through the activation of receptors in the spinal cord andhigher pain centres in the brain. Increasing endogenous levels ofacetylcholine through acetylcholinesterase inhibitors, direct activationof muscarinic receptors with agonists or allosteric modulators has beenshown to have analgesic activity. In contrast blockade of muscarinicreceptors with antagonists or using knockout mice increases painsensitivity. Evidence for the role of the M1 receptor in pain isreviewed by D. F. Fiorino and M. Garcia-Guzman, 2012.

More recently, a small number of compounds have been identified whichdisplay improved selectivity for the M₁ mAChR subtype over theperipherally expressed mAChR subtypes (Bridges et al., 2008 Bioorg MedChem Lett; Johnson at al., 2010 Bioorg Med Chem Lett; Budzik et al.,2010 ACS Med Chem Lett). Despite increased levels of selectivity versusthe M₃ mAChR subtype, some of these compounds retain significant agonistactivity at both this subtype and the M₂ mAChR subtype. Herein wedescribe a series of compounds which unexpectedly display high levels ofselectivity for the M₁ mAChR over the M₂ and M₃ receptor subtypes.

SUMMARY OF THE INVENTION

The present invention provides compounds having activity as muscarinicM1 receptor agonists. More particularly, the invention providescompounds that exhibit selectivity for the M1 receptor relative to theM2, M3 and M4 receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1):

or a salt thereof, wherein:n is 1 or 2;p is 0, 1 or 2;q is 0, 1 or 2;R¹ is a C₁₋₁₀ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof;R² is hydrogen or a C₁₋₁₀ non-aromatic hydrocarbon group;or R¹ and R² together with the nitrogen atom to which they are attachedform a non-aromatic heterocyclic group of four to nine ring members,wherein the heterocyclic ring may optionally contain a second heteroatomselected from O, N and S and oxidised forms thereof; and wherein theheterocyclic ring may optionally be substituted with one to six moresubstitutents selected from C₁₋₂ alkyl; fluorine; and cyano;R³ is selected from hydrogen; halogen; cyano; hydroxy; C₁₋₃ alkoxy; anda C₁₋₅ non-aromatic hydrocarbon group which is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S;R⁴ is a C₁₋₆ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof;R⁵ is absent or is fluorine; andR⁶ is absent or is fluorine.

FIGURES

FIGS. 1-4 show the efficacy of the compounds of the invention. FIGS. 1-3relate to the passive avoidance assay described in part B. Studies werecarried out as described previously by Foley et al. (2004)Neuropsychopharmacology. In the passive avoidance task scopolamineadministration (1 mg/kg, i.p.) at 6 hours following training renderedanimals amnesic of the paradigm. A dose range of 3, 10, and 30 mg/kg(po) free base, administered 90 minutes prior to the training period viaoral gavage, was examined.

FIG. 1 shows that Example 27 was found to reverse scopolamine-inducedamnesia of the paradigm in a dose-dependent manner, with an approximateED₅₀ of ca. 10 mg/kg (po). The effect of 30 mg/kg was similar to thatproduced by the cholinesterase inhibitor donepezil (0.1 mg/kg, ip) whichserved as a positive control.

FIG. 2 shows that Example 65 was found to reverse scopolamine-inducedamnesia of the paradigm in a dose-dependent manner, with significanteffects observed after acute administration of 10 and 30 mg/kg (p<0.05;Bonferroni post hoc test). The effect at 10 and 30 mg/kg was notsignificantly different to that produced by the cholinesterase inhibitordonepezil (0.1 mg/kg, i.p.), which served as a positive control.

FIG. 3 shows that Example 65 was found to reverse scopolamine-inducedamnesia in a dose-dependent manner, with significant effects observedafter acute administration of 10 mg/kg (po) (p<0.05; Bonferroni post hoctest). The effect at 10 mg/kg was not significantly different to thatproduced by the cholinesterase inhibitor donepezil (0.1 mg/kg, i.p.),which served as a positive control. Combination of Example 65 anddonepezil did not result in a loss of activity, rather the combinationhad an additive effect at each dose combination as analysed by MannWhitney u-test.

FIG. 4 shows the effects of Example 65 in a rodent object recognitionassay described in Example D. Statistical analysis determined thattreatment with 10 and 30 mg/kg for Example 65 and 3 mg/kg of thepositive control galanthamine significantly improved novel objectrecognition memory when compared to vehicle-treated controls (p<0.05).Donepezil (0.1 mg/kg) was without effect on novel object recognition.During the 10 minute training period in the apparatus, animals werescored for exploratory behaviour. There was no difference as regardsexploration for either object or between vehicle-treated controls andany drug treatment group.

DETAILED DESCRIPTION

The present invention provides compounds having activity as muscarinicM1 receptor agonists. More particularly, the invention providescompounds that exhibit selectivity for the M1 receptor relative to theM2, M3 and M4 receptor subtypes.

Accordingly, in a first embodiment (Embodiment 1.1), the inventionprovides a compound of the formula (1):

or a salt thereof, wherein:n is 1 or 2:p is 0, 1 or 2;q is 0, 1 or 2;R¹ is a C₁₋₁₀ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof;R² is hydrogen or a C₁₋₁₀ non-aromatic hydrocarbon group;or R¹ and R² together with the nitrogen atom to which they are attachedform a non-aromatic heterocyclic group of four to nine ring members,wherein the heterocyclic ring may optionally contain a second heteroatomselected from O, N and S and oxidised forms thereof; and wherein theheterocyclic ring may optionally be substituted with one to six moresubstitutents selected from C₁₋₂ alkyl; fluorine; and cyano;R³ is selected from hydrogen; halogen; cyano; hydroxy; C₁₋₃ alkoxy; anda C₁₋₅ non-aromatic hydrocarbon group which is optionally substitutedwith one to six fluorine atoms and wherein one or two, but not all,carbon atoms of the hydrocarbon group may optionally be replaced by aheteroatom selected from O, N and S;R⁴ is a C₁₋₆ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof;R⁵ is absent or is fluorine; andR⁶ is absent or is fluorine.

Particular and preferred compounds of the formula (1) are as defined inthe following Embodiments 1.2 to 1.53:

1.2 A compound according to Embodiment 1.1 wherein n is 1.

1.3 A compound according to Embodiment 1.1 wherein n is 2.

1.4 A compound according to any one of Embodiments 1.1 to 1.3 wherein R¹is a C₁₋₁₀ non-aromatic hydrocarbon group which is optionallysubstituted with one to six fluorine atoms and wherein one or two, butnot all, carbon atoms of the hydrocarbon group may optionally bereplaced by a heteroatom selected from O, N and S and oxidised formsthereof; the C₁₋₁₀ non-aromatic hydrocarbon group containing 0, 1 or 2carbon-carbon multiple bonds.

1.5 A compound according to any one of Embodiments 1.1 to 1.4 wherein R¹is selected from C₁₋₆ alkyl; C₂₋₆ alkenyl; C₂₋₆ alkynyl; and C₁₋₁₀non-aromatic hydrocarbon groups consisting of or containing a C₃₋₁₀cycloalkyl or C₅₋₆ cycloalkenyl group; each of the said alkyl, alkenyl,alkynyl and non-aromatic hydrocarbon groups being optionally substitutedwith one to six fluorine atoms; and wherein one or two, but not all,carbon atoms of each of the alkyl, alkenyl, alkynyl and non-aromatichydrocarbon groups may optionally be replaced by a heteroatom selectedfrom O, N and S and oxidised forms thereof.

1.6 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹is selected from:

-   -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;    -   methoxy-C₁₋₄ alkyl optionally substituted with 1 to 6 fluorine        atoms;    -   C₁₋₆ alkoxy;    -   C₂₋₆ alkenyl;    -   C₂₋₆ alkynyl;    -   C₃₋₆ cycloalkyl optionally substituted with one or two methyl        groups;    -   C₄₋₅ cycloalkyl-CH₂— wherein the C₄₋₅ cycloalkyl moiety is        optionally substituted with one C₁₋₂ alkyl group and wherein one        carbon atom of the C₄₋₅ cycloalkyl moiety may optionally be        replaced by an oxygen atom;    -   cyclopropyl-C₁₋₃ alkyl;    -   cyclopentenyl; and    -   methyl-bicyclo[2.2.2]octanyl.

1.7 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹is selected from:

-   -   C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms;    -   C₃₋₆ cycloalkyl optionally substituted with one or two methyl        groups;    -   C₄₋₅ cycloalkyl-CH₂— wherein the C₄₋₅ cycloalkyl moiety is        optionally substituted with one C₁₋₂ alkyl group and wherein one        carbon atom of the C₄₋₅ cycloalkyl moiety may optionally be        replaced by an oxygen atom;    -   a cyclopropyl-C₁₋₃ alkyl; and    -   cyclopentenyl; and    -   methyl-bicyclo[2.2.2]octanyl.

1.8 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹is C₁₋₆ alkyl optionally substituted with 1 to 6 fluorine atoms.

1.9 A compound according to any one of Embodiments 1.1 to 1.5 wherein R¹is C₃₋₆ cycloalkyl optionally substituted with one or two methyl groups.

1.10 A compound according to any one of Embodiments 1.1 to 1.5 whereinR¹ is C₄₋₅ cycloalkyl-CH₂— wherein the C₄₋₅ cycloalkyl moiety isoptionally substituted with one C₁₋₂ alkyl group and wherein one carbonatom of the C₄₋₅ cycloalkyl moiety may optionally be replaced by anoxygen atom.

1.11 A compound according to any one of Embodiments 1.1 to 1.5 whereinR¹ is cyclopropyl-C₁₋₃ alkyl.

1.12 A compound according to any one of Embodiments 1.1 to 1.5 whereinR¹ is methyl-bicyclo[2.2.2]octanyl.

1.13 A compound according to any one of Embodiments 1.1 to 1.5 whereinR¹ is selected from groups A to AS below:

where the asterisk denotes the point of attachment of the group to theamide nitrogen atom.

1.14 A compound according to Embodiment 1.13 wherein R¹ is selected fromgroups A, B, D, E, F, G, L, M, N, O, Q, R, T, V, W, Y, AA, AB, AC, AJ,AK, AO, AR and AR (wherein R¹ is selected from 2-methylpropyl,tert-butyl, 2-methylbutyl, 2,2-dimethylpropyl, 2-methylbut-2-yl,cyclobutylmethyl, cyclopropylmethyl, cyclopentylmethyl, isopropyl,1-methylcyclohexyl, 1-methylcyclopentylmethyl, 2-cyclopropylpropyl,1-methylcyclobutyl, cyclopentyl, 2,3-dimethylbutan-2-yl,1-ethylcyclobutylmethyl, 1-methylcyclopentyl, 2-cyclopropylpropan-2-yl,cyclobutyl, 1-methylcyclobutylmethyl, 1-(trifluoromethyl)cyclobutyl,1-ethylcyclobutyl, (²H₃)methyl(²H₆)propyl and 2-methylpentan-2-ylgroups).

1.15 A compound according to any one of Embodiments 1.1 to 1.6 whereinR¹ is selected from 2-methylpropyl; 2,2-dimethylpropyl; tert-butyl;2-methyl-but-2-yl; 2,3-dimethylbut-2-yl; cyclopropylmethyl;cyclobutylmethyl; cyclopentyl; cyclopentylmethyl; 1-methylcyclobutyl,1-methylcyclopentyl; 1 methylcyclohexyl; 1-methylcyclopentylmethyl;cyclopropyl-prop-2-yl; and 1-ethyl-cyclobutylmethyl groups.

1.15a A compound according to 1.14 wherein R¹ is selected from groups A,F, G, O, R, T, V, W, Y, AA, AB, AJ, AO and AR (wherein R¹ is selectedfrom 2-methylpropyl, 2-methylbut-2-yl, cyclobutylmethyl,1-methylcyclohexyl, 2-cyclopropylpropyl, 1-methylcyclobutyl,cyclopentyl, 2,3-dimethylbutan-2-yl, 1-ethylcyclobutylmethyl,1-methylcyclopentyl, 2-cyclopropylpropan-2-yl, 1-methylcyclobutylmethyland 1-ethylcyclobutyl and (²H₃)methyl(²H₆)propyl groups).

1.16 A compound according to Embodiment 1.15 or 1.15a wherein R¹ isselected from 2-methylpropyl and 1-methylcyclobutyl.

1.17 A compound according to Embodiment 1.16 wherein R¹ is2-methylpropyl.

1.18 A compound according to Embodiment 1.16 wherein R¹ is1-methylcyclobutyl.

1.19 A compound according to any one of Embodiments 1.1 to 1.18 whereinR² is selected from hydrogen and C₁₋₆ alkyl.

1.20 A compound according to Embodiment 1.19 wherein R² is selected fromhydrogen, methyl, ethyl and isopropyl.

1.21 A compound according to Embodiment 1.20 wherein R² is hydrogen.

1.22 A compound according to any one of Embodiments 1.1 to 1.21 whereinR³ is selected from hydrogen, halogen, cyano, hydroxy, C₁₋₃ alkoxy andC₁₋₄ alkyl.

1.23 A compound according to Embodiment 1.22 wherein R³ is selected fromhydrogen, fluorine and methyl, cyano and methoxy.

1.23a A compound according to Embodiment 1.22 wherein R³ is selectedfrom hydrogen, fluorine and methyl, cyano and methoxy and R¹ is1-methylcyclobutyl.

1.24 A compound according to Embodiment 1.23 or 1.23a wherein R³ isselected from hydrogen and fluorine.

1.25 A compound according to Embodiment 1.24 wherein R³ is hydrogen.

1.26 A compound according to Embodiment 1.24 wherein R³ is fluorine.

1.27 A compound according to any one of Embodiments 1.1 to 1.26 whereinR⁴ is an acyclic C₁₋₆ hydrocarbon group.

1.28 A compound according to Embodiment 1.27 wherein R⁴ is an acyclicC₁₋₃ hydrocarbon group.

1.29 A compound according to Embodiment 1.20 wherein R⁴ is a C₁₋₃ alkylgroup or a C₂₋₃ alkynyl group.

1.30 A compound according to Embodiment 1.29 wherein R⁴ is selected frommethyl, ethyl, ethynyl and 1-propynyl.

1.31 A compound according to Embodiment 1.30 wherein R⁴ is methyl.

1.32 A compound according to any one of Embodiments 1.1 to 1.31 whereinR⁵ is fluorine.

1.33 A compound according to any one of Embodiments 1.1 to 1.32 whereinp is 0 or 1.

1.34 A compound according to any one of Embodiments 1.1 to 1.31 whereinp is 0.

1.35 A compound according to any one of Embodiments 1.1 to 1.32 whereinp is 1.

1.36 A compound according to any one of Embodiments 1.1 to 1.35 whereinR⁶ is fluorine.

1.37 A compound according to any one of Embodiments 1.1 to 1.36 whereinq is 0 or 1.

1.38 A compound according to any one of Embodiments 1.1 to 1.35 whereinq is 0.

1.39 A compound according to any one of Embodiments 1.1 to 1.36 whereinq is 1.

1.40 A compound according to Embodiment 1.1 having the formula (2):

wherein R¹, R³, R⁴, R⁵, R⁶, p and q are as defined in any one ofEmbodiments 1.1 and 1.3 to 1.39.1.41 A compound according to Embodiment 1.40 having the formula (3):

wherein R¹, R³, R⁴, R⁵, R⁶, p and q are as defined in any one ofEmbodiments 1.1 and 1.3 to 1.39.1.42 A compound according to Embodiment 1.40 having the formula (4):

wherein R¹, R³, R⁴, R⁵, R³, p and q are as defined in any one ofEmbodiments 1.1 and 1.3 to 1.39.1.43 A compound according to Embodiment 1.1 which is as defined in anyone of Examples 1 to 64.1.43a A compound according to Embodiment 1.1 which is as defined in anyone of Examples 65 to 32.1.43b A compound according to Embodiment 11 which is as defined in anyone of Examples 1 to 82.1.44 A compound according to Embodiment 1.43 which is selected from thecompounds of Examples 6, 7, 8, 9, 10, 11, 15, 16, 17, 18, 27, 30, 31,37, 39, 40, 41, 42, 43, 44, 45, 46, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 63 and 64 and salts thereof or a compound according toEmbodiment 1.43a which is selected from the compounds of Examples 65,66, 67, 73, 74, 75, 77, 78, 79, 80, 81 and 82 and salts thereof.1.45 A compound according to Embodiment 1.44 which is ethyl4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate ora salt thereof.1.46 A compound according to Embodiment 1.45 which is ethyl(4S)-4-[4-((2-methylpropyl)methylcarbamoyl)piperidin-1-yl]azepane-1-carboxylateor a salt thereof.1.47 A compound according to Embodiment 1.45 which is ethyl(4R)-4-[4-((2-methylpropyl)methylcarbamoyl)piperidin-1-yl]azepane-1-carboxylateor a salt thereof.1.48 A compound according to Embodiment 1.44 which is ethyl4-(4-((1-methylcyclobutyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylateor a salt thereof.1.48a A compound according to Embodiment 1.48 which is ethyl(4S)-4-[4-[(1-methylcyclobutyl)carbamoyl]-1-piperidyl]azepane-1-carboxylateor a salt thereof.1.49 A compound according to any one of Embodiments 1.1 to 1.48a havinga molecular weight of less than 550, for example less than 500, or lessthan 450.1.50 A compound according to any one of Embodiments 1.1 to 1.49 which isin the form of a salt.1.51 A compound according to Embodiment 1.50 wherein the salt is an acidaddition salt.1.52 A compound according to Embodiment 1.50 or Embodiment 1.51 whereinthe salt is a pharmaceutically acceptable salt.

Definitions

In this application, the following definitions apply, unless indicatedotherwise.

The term “treatment” in relation to the uses of the compounds of theformula (1), is used to describe any form of intervention where acompound is administered to a subject suffering from, or at risk ofsuffering from, or potentially at risk of suffering from the disease ordisorder in question. Thus, the term “treatment” covers bothpreventative (prophylactic) treatment and treatment where measurable ordetectable symptoms of the disease or disorder are being displayed.

The term “non-aromatic hydrocarbon group” (as in “C₁₋₁₀ non-aromatichydrocarbon group” or “acyclic C₁₋₅ non-aromatic hydrocarbon group”)refers to a group consisting of carbon and hydrogen atoms and whichcontains no aromatic rings. The hydrocarbon group may be fully saturatedor may contain one or more carbon-carbon double bonds or carbon-carbontriple bonds, or mixtures of double and triple bonds. The hydrocarbongroup may be a straight chain or branched chain group or may consist ofor contain a cyclic group.

The term “cycloalkyl” as used herein, where the specified number ofcarbon atoms permits, includes both monocyclic cycloalkyl groups such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, andbicyclic and tricyclic groups. Bicyclic cycloalkyl groups includebridged ring systems such as bicycloheptane, bicyclooctane andadamantane.

Salts

Many compounds of the formula (1) can exist in the form of salts, forexample acid addition salts or, in certain cases salts of organic andinorganic bases such as carboxylate, sulfonate and phosphate salts. Allsuch salts are within the scope of this invention, and references tocompounds of the formula (1) include the salt forms of the compounds asdefined in Embodiments 1.50 to 1.53.

The salts are typically acid addition salts.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used.

Acid addition salts (as defined in Embodiment 1.51) may be formed with awide variety of acids, both inorganic and organic. Examples of acidaddition salts falling within Embodiment 1.51 include mono- or di-saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1 S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, acetyl leucine, maleic, malic, (−)-L-malic, malonic,(±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic,naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulfuric, tannic, (+)-L-tartaric, (−)-D-tartaric,(−)-dibenzoyltartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.

Where the compounds of the formula (1) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (1).

The compounds of the invention may exist as mono- or di-salts dependingupon the pKa of the acid from which the salt is formed.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al., 1977, “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci, Vol. 66, pp. 1-19. However, salts thatare not pharmaceutically acceptable may also be prepared as intermediateforms which may then be converted into pharmaceutically acceptablesalts. Such non-pharmaceutically acceptable salts forms, which may beuseful, for example, in the purification or separation of the compoundsof the invention, also form part of the invention.

Stereoisomers

Stereoisomers are isomeric molecules that have the same molecularformula and sequence of bonded atoms but which differ only in thethree-dimensional orientations of their atoms in space. Thestereoisomers can be, for example, geometric isomers or optical isomers.

Geometric Isomers

With geometric isomers, the isomerism is due to the differentorientations of an atom or group about a double bond, as in cis andtrans (Z and E) isomerism about a carbon-carbon double bond, or cis andtrans isomers about an amide bond, or syn and anti isomerism about acarbon nitrogen double bond (e.g. in an oxime), or rotational isomerismabout a bond where there is restricted rotation, or cis and transisomerism about a ring such as a cycloalkane ring.

Accordingly, in another embodiment (Embodiment 1.53a), the inventionprovides a geometric isomer of a compound according to any one ofEmbodiments 1.1 to 1.53.

Optical Isomers

Where compounds of the formula contain one or more chiral centres, andcan exist in the form of two or more optical isomers, references to thecompounds include all optical isomeric forms thereof (e.g. enantiomers,epimers and diastereoisomers), either as individual optical isomers, ormixtures (e.g. racemic mixtures) or two or more optical isomers, unlessthe context requires otherwise.

Accordingly, in another embodiment (Embodiment 1.54) the inventionprovides a compound according to any one of Embodiments 1.1 to 1.53which contains a chiral centre.

The optical isomers may be characterised and identified by their opticalactivity (i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog, Angew.Chem. Mt. Ed. Engl., 1966, 5, 385-415. Optical isomers can be separatedby a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-tartaric acid, acetyl leucine, (−)-pyroglutamic acid,(−)-di-toluoyl-L-tartaric acid, (+)-mandelic acid, (−)-malic acid, and(−)-camphorsulphonic, separating the diastereoisomers by preferentialcrystallisation, and then dissociating the salts to give the individualenantiomer of the free base.

Where compounds of the invention exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers.

Accordingly, in another embodiment (Embodiment 1.55), the inventionprovides compositions containing a compound according to Embodiment 1.54having one or more chiral centres, wherein at least 55% (e.g. at least60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of Embodiment1.54 is present as a single optical isomer (e.g. enantiomer ordiastereoisomer).

In one general embodiment (Embodiment 1.56), 99% or more (e.g.substantially all) of the total amount of the compound (or compound foruse) of Embodiment 1.54 is present as a single optical isomer.

For example, in one embodiment (Embodiment 1.57) the compound is presentas a single enantiomer.

In another embodiment (Embodiment 1.58), the compound is present as asingle diastereoisomer.

The invention also provides mixtures of optical isomers, which may beracemic or non-racemic. Thus, the invention provides:

1.59 A compound according to Embodiment 1.54 which is in the form of aracemic mixture of optical isomers.

1.60 A compound according to Embodiment 1.54 which is in the form of anon-racemic mixture of optical isomers.

Isotopes

The compounds of the invention as defined in any one of Embodiments 1.1to 1.60 may contain one or more isotopic substitutions, and a referenceto a particular element includes within its scope all isotopes of theelement. For example, a reference to hydrogen includes within its scope¹H, ²H (D), and ³H (T). Similarly, references to carbon and oxygeninclude within their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and¹⁸O.

In an analogous manner, a reference to a particular functional groupalso includes within its scope isotopic variations, unless the contextindicates otherwise. For example, a reference to an alkyl group such asan ethyl group also covers variations in which one or more of thehydrogen atoms in the group is in the form of a deuterium or tritiumisotope, e.g. as in an ethyl group in which all five hydrogen atoms arein the deuterium isotopic form (a perdeuteroethyl group).

The isotopes may be radioactive or non-radioactive. In one embodiment ofthe invention (Embodiment 1.61), the compound of any one of Embodiments1.1 to 1.60 contains no radioactive isotopes. Such compounds arepreferred for therapeutic use. In another embodiment (Embodiment 1.62),however, the compound of any one of Embodiments 1.1 to 1.60 may containone or more radioisotopes. Compounds containing such radioisotopes maybe useful in a diagnostic context.

Solvates

Compounds of the formula (1) as defined in any one of Embodiments 1.1 to1.62 may form solvates. Preferred solvates are solvates formed by theincorporation into the solid state structure (e.g. crystal structure) ofthe compounds of the invention of molecules of a non-toxicpharmaceutically acceptable solvent (referred to below as the solvatingsolvent). Examples of such solvents include water, alcohols (such asethanol, isopropanol and butanol) and dimethylsulphoxide. Solvates canbe prepared by recrystallising the compounds of the invention with asolvent or mixture of solvents containing the solvating solvent. Whetheror not a solvate has been formed in any given instance can be determinedby subjecting crystals of the compound to analysis using well known andstandard techniques such as thermogravimetric analysis (TOE),differential scanning calorimetry (DSC) and X-ray crystallography. Thesolvates can be stoichiometric or non-stoichiometric solvates.Particularly preferred solvates are hydrates, and examples of hydratesinclude hemihydrates, monohydrates and dihydrates.

Accordingly, in further embodiments 1.63 and 1.64, the inventionprovides:

1.63 A compound according to any one of Embodiments 1.1 to 1.62 in theform of a solvate.

1.64 A compound according to Embodiment 1.63 wherein the solvate is ahydrate.

For a more detailed discussion of solvates and the methods used to makeand characterise them, see Bryn et al., Solid-State Chemistry of Drugs,Second Edition, published by SSCI, Inc of West Lafayette, Ind., USA,1999, ISBN 0-967-06710-3.

Alternatively, rather than existing as a hydrate, the compound of theinvention may be anhydrous. Therefore, in another embodiment (Embodiment1.65), the invention provides a compound as defined in any one ofEmbodiments 1.1 to 1.62 in an anhydrous form (e.g. anhydrous crystallineform).

Crystalline and Amorphous Forms

The compounds of any one of Embodiments 1.1 to 1.65 may exist in acrystalline or non-crystalline (e.g. amorphous) state. Whether or not acompound exists in a crystalline state can readily be determined bystandard techniques such as X-ray powder diffraction (XRPD). Crystalsand their crystal structures can be characterised using a number oftechniques including single crystal X-ray crystallography, X-ray powderdiffraction (XRPD), differential scanning calorimetry (DSC) and infrared spectroscopy, e.g. Fourier Transform infra-red spectroscopy (FTIR).The behaviour of the crystals under conditions of varying humidity canbe analysed by gravimetric vapour sorption studies and also by XRPD,Determination of the crystal structure of a compound can be performed byX-ray crystallography which can be carried out according to conventionalmethods such as those described herein and as described in Fundamentalsof Crystallography, C. Giacovazzo, H. L. Monaco, D. Viterbo, F.Scordari, G. Gilli, G. Zanotti and M. Catti, (International Union ofCrystallography/Oxford University Press, 1992 ISBN 0-19-855578-4 (p/b),0-19-85579-2 (h/b)). This technique involves the analysis andinterpretation of the X-ray diffraction of single crystal. In anamorphous solid, the three dimensional structure that normally exists ina crystalline form does not exist and the positions of the moleculesrelative to one another in the amorphous form are essentially random,see for example Hancock et a. J. Pharm. Sci. (1997), 86, 1).

Accordingly, in further embodiments, the invention provides:

1.66 A compound according to any one of Embodiments 1.1 to 1.65 in acrystalline form.

1.67 A compound according to any one of Embodiments 1.1 to 1.65 whichis:

(a) from 50% to 100% crystalline, and more particularly is at least 50%crystalline, or at least 60% crystalline, or at least 70% crystalline,or at least 80% crystalline, or at least 90% crystalline, or at least95% crystalline, or at least 98% crystalline, or at least 99%crystalline, or at least 99.5% crystalline, or at least 99.9%crystalline, for example 100% crystalline.

1.68 A compound according to any one of Embodiments 1.1 to 1.65 which isin an amorphous form.

Prodrugs

The compounds of the formula (1) as defined in any one of Embodiments1.1 to 1.62 may be presented in the form of a pro-drug. By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (1), as defined in any oneof Embodiments 1.1 to 1.62.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). Duringmetabolism, the ester group (—C(═O)OR) is cleaved to yield the activedrug. Such esters may be formed by esterification, for example, of anyhydroxyl groups present in the parent compound with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Also, some prodrugs are activated enzymatically to yield the activecompound, or a compound which, upon further chemical reaction, yieldsthe active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.), Forexample, the prodrug may be a sugar derivative or other glycosideconjugate, or may be an amino acid ester derivative.

Accordingly, in another embodiment (Embodiment 1.69), the inventionprovides a pro-drug of a compound as defined in any one of Embodiments1.1 to 1.62 wherein the compound contains a functional group which isconvertable under physiological conditions to form a hydroxyl group oramino group.

Complexes and Clathrates

Also encompassed by formula (1) in Embodiments 1.1 to 1.69 are complexes(e.g. inclusion complexes or clathrates with compounds such ascyclodextrins, or complexes with metals) of the compounds of Embodiments1.1 to 1.69.

Accordingly, in another embodiment (Embodiment 1.70), the inventionprovides a compound according to any one of Embodiments 1.1 to 1.69 inthe form of a complex or clathrate,

Biological Activity and Therapeutic Uses

The compounds of the present invention have activity as muscarinic M1receptor agonists. The muscarinic activity of the compounds can bedetermined using the Phospho-ERK1/2 assay described in Example A below.

A significant advantage of compounds of the invention is that they haveselectivity for the M1 receptor relative to the M2 and M3 receptorsubtypes. For example, whereas compounds of the invention typically havepEC₅₀ values of at least 6 (preferably at least 6.5) and E_(max) valuesof greater than 80 (preferably greater than 100) against the M1 receptorin the functional assay described in Example A, they may have pEC₅₀values of less than 6 (and usually less than 5) and E_(max) values ofless than 50% when tested against the M2 and M3 subtypes in thefunctional assay of Example A.

Accordingly, in Embodiments 2.1 to 2.9, the invention provides:

2.1 A compound according to any one of Embodiments 1.1 to 1.70 for usein medicine.

2.2 A compound according to any one of Embodiments 1.1 to 1.70 for useas a muscarinic M1 receptor agonist.

2.3 A compound according to any one of Embodiments 1.1 to 1.70 which isa muscarinic M1 receptor agonist having a pEC₅₀ in the range from 6.0 to7.9 and an E_(max) of at least 90 against the M1 receptor in the assayof Example A herein or an assay substantially similar thereto.

2.4 A compound according to Embodiment 2.3 which is a muscarinic M1receptor agonist having a pEC₅₀ in the range from 6.5 to 7.5.

2.4a A compound according to Embodiment 2.3 which is a muscarinic M1receptor agonist having a pEC50 in the range from 6.8 to 7.9.

2.4b A compound according to Embodiment 2.3 which is a muscarinic M1receptor agonist having a pEC50 in the range from 7.1 to 7.9.

2.5 A compound according to Embodiment 2.3, Embodiment 2.4, Embodiment2.4a or Embodiment 2.4b having an E_(max) of at least 100 against the M1receptor.

2.6 A compound according to any one of Embodiments 2.3 to 2.5 which isselective for the M1 receptor compared to the muscarinic M2 and M3receptors.

2.7 A compound according to any one of Embodiments 2.3 to 2.6 which hasa pEC₅n of less than 5 and an E_(max) of less than 50 against themuscarinic M2 and M3 receptor subtypes.

2.8 A compound according to Embodiment 2.7 which has a pEC₅₀ of lessthan 4.5 and/or an E_(max) of less than 30 against the muscarinic M2 andM3 receptor subtypes.

2.9 A compound according to any one of Embodiments 1.1 to 1.70 andEmbodiments 2.3 to 2.8 for use in the treatment of a disease orcondition mediated by the muscarinic M1 receptor.

By virtue of their muscarinic M1 receptor agonist activity, compounds ofthe invention can be used in the treatment of Alzheimer's disease,schizophrenia and other psychotic disorders, cognitive disorders andother diseases mediated by the muscarinic M1 receptor.

Accordingly, in Embodiments 2.10 to 2.13, the invention provides:

2.10 A compound according to any one of Embodiments 1.1 to 1.70 for usein the treatment of a cognitive disorder or psychotic disorder.

2.11 A compound for use in according to Embodiment 2.10 wherein thecognitive disorder or psychotic disorder comprises, arises from or isassociated with a condition selected from cognitive impairment, mildcognitive impairment, frontotemporal dementia, vascular dementia,dementia with Lewy bodies, presenile dementia, senile dementia,Friederich's ataxia, Down's syndrome, Huntington's chorea, hyperkinesia,mania, Tourette's syndrome, Alzheimer's disease, progressivesupranuclear palsy, impairment of cognitive functions includingattention, orientation, learning disorders, memory (i.e. memorydisorders, amnesia, amnesic disorders, transient global amnesia syndromeand age-associated memory impairment) and language function; cognitiveimpairment as a result of stroke, Huntington's disease, Pick disease,Aids-related dementia or other dementia states such as multiinfarctdementia, alcoholic dementia, hypothyroidism-related dementia, anddementia associated with other degenerative disorders such as cerebellaratrophy and amyotropic lateral sclerosis; other acute or sub-acuteconditions that may cause cognitive decline such as delirium ordepression (pseudodementia states) trauma, head trauma, age relatedcognitive decline, stroke, neurodegeneration, drug-induced states,neurotoxic agents, age related cognitive impairment, autism relatedcognitive impairment, Down's syndrome, cognitive deficit related topsychosis, and post-electroconvulsive treatment related cognitivedisorders; cognitive disorders due to drug abuse or drug withdrawalincluding nicotine, cannabis, amphetamine, cocaine, Attention DeficitHyperactivity Disorder (ADHD) and dyskinetic disorders such asParkinson's disease, neuroleptic-induced parkinsonism, and tardivedyskinesias, schizophrenia, schizophreniform diseases, psychoticdepression, mania, acute mania, paranoid, hallucinogenic and delusionaldisorders, personality disorders, obsessive compulsive disorders,schizotypal disorders, delusional disorders, psychosis due tomalignancy, metabolic disorder, endocrine disease or narcolepsy,psychosis due to drug abuse or drug withdrawal, bipolar disorders andschizo-affective disorder.

2.12 A compound according to any one of Embodiments 1.1 to 1.70 for usein the treatment of Alzheimer's disease.

2.13 A compound according to any one of Embodiments 1.1 to 1.70 for usein the treatment of Schizophrenia.

2.14 A method of treatment of a cognitive disorder in a subject (e.g. amammalian patient such as a human, e.g. a human in need of suchtreatment), which method comprises the administration of atherapeutically effective dose of a compound according to any one ofEmbodiments 1.1 to 1.70.

2.15 A method according to Embodiment 2.14 wherein the cognitivedisorder comprises, arises from or is associated with a condition asdefined in Embodiment 2.11.

2.16 A method according to Embodiment 2.15 wherein the cognitivedisorder arises from or is associated with Alzheimer's disease.

2.17 A method according to Embodiment 2.16 wherein the cognitivedisorder is Schizophrenia.

2.18 The use of a compound according to any one of Embodiments 1.1 to1.70 for the manufacture of a medicament for the treatment of acognitive disorder.

2.19 The use according to Embodiment 2.10 wherein the cognitive disordercomprises, arises from or is associated with a condition as defined inEmbodiment 2.11.

2.20 The use according to Embodiment 2.19 wherein the cognitive disorderarises from or is associated with Alzheimer's disease.

2.21 The use according to Embodiments 2.19 wherein the cognitivedisorder is Schizophrenia.

2.22 A compound according to any one of Embodiments 1.1 to 1.70 for thetreatment or lessening the severity of acute, chronic, neuropathic, orinflammatory pain, arthritis, migraine, cluster headaches, trigeminalneuralgia, herpetic neuralgia, general neuralgias, visceral pain,osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy,radicular pain, sciatica, back pain, head or neck pain, severe orintractable pain, nociceptive pain, breakthrough pain, Postsurgicalpain, or cancer pain.

2.23 A method of treatment or lessening the severity of acute, chronic,neuropathic, or inflammatory pain, arthritis, migraine, clusterheadaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias,visceral pain, osteoarthritis pain, postherpetic neuralgia, diabeticneuropathy, radicular pain, sciatica, back pain, head or neck pain,severe or intractable pain, nociceptive pain, breakthrough pain,postsurgical pain, or cancer pain, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.70.

2.24 A compound according to any one of Embodiments 1.1 to 1.70 for thetreatment of peripheral disorders such as reduction of intra ocularpressure in glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

2.25 A method of treatment of peripheral disorders such as reduction ofintra ocular pressure in glaucoma and treatment of dry eyes and drymouth including Sjogren's Syndrome, which method comprises theadministration of a therapeutically effective dose of a compoundaccording to any one of Embodiments 1.1 to 1.70.

2.26 The use of a compound according to any one of Embodiments 1.1 to1.70 for the manufacture of a medicament for the treatment or lesseningthe severity of acute, chronic, neuropathic, or inflammatory pain,arthritis, migraine, cluster headaches, trigeminal neuralgia, herpeticneuralgia, general neuralgias, visceral pain, osteoarthritis pain,postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica,back pain, head or neck pain, severe or intractable pain, nociceptivepain, breakthrough pain, postsurgical pain, or cancer pain or for thetreatment of peripheral disorders such as reduction of intra ocularpressure in glaucoma and treatment of dry eyes and dry mouth includingSjogren's Syndrome.

Methods for the Preparation of Compounds of the Formula (1)

Compounds of the formula (1) can be prepared in accordance withsynthetic methods well known to the skilled person and as describedherein.

Accordingly, in another embodiment (Embodiment 3.1), the inventionprovides a process for the preparation of a compound as defined in anyone of Embodiments 1.1 to 1.70, which process comprises:

(A) the reaction of a compound of the formula (10)

wherein R³, R⁴, R⁵ and R⁶ are as defined in any one of Embodiments 1.1to 1.70 with a compound of the formula R¹R²NH under amide-formingconditions; or(B) the reaction of a compound of the formula (11):

with a compound of the formula Cl—C(═O)O—CH₂—R⁴, in the presence of abase; and optionally:(C) converting one compound of the formula (1) to another compound ofthe formula (1).

In process variant (A), the reaction may be carried out in the presenceof a reagent of the type commonly used in the formation of amide bonds.Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC)(Sheehan et al, J. Amer. Chem Soc. 1955, 77, 1067),1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide (referred to hereineither as EDC or EDAC) (Sheehan et at, J. Org. Chem., 1961, 26, 2525),uronium-based coupling agents such asO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and phosphonium-based coupling agents such as1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate(PyBOP) (Castro et al, Tetrahedron Letters, 1990, 31, 205).Carbodiimide-based coupling agents are advantageously used incombination with 1-hydroxy-7-azabenzotriazole (HOAt) (L. A. Carpino, J.Amer. Chem. Soc., 1993, 115, 4397) or 1-hydroxybenzotriazole (HOBt)(Konig et al, Chem. Ber., 103, 708, 2024-2034). A preferred amidecoupling agent is HATU.

The coupling reaction is typically carried out in a non-aqueous,non-protic solvent such as acetonitrile, dioxane, dimethylsulphoxide,dichloromethane, dimethylformamide or N-methylpyrrolidinone, or in anaqueous solvent optionally together with one or more miscibleco-solvents. The reaction can be carried out at room temperature or,where the reactants are less reactive at an appropriately elevatedtemperature, for example a temperature up to about 100° C., e.g. 50-80°C. The reaction may optionally be carried out in the presence of anon-interfering base, for example a tertiary amine such as triethylamineor N,N-diisopropylethylamine.

As an alternative, a reactive derivative of the carboxylic acid, e.g. ananhydride or acid chloride, may be used. The acid chloride is typicallyreacted with the compound of formula R¹R²NH in the presence of a basesuch as sodium bicarbonate or sodium hydroxide. The acid chloride can beprepared using standard methods, for example by treatment of the acidwith oxalyl chloride in the presence of a catalytic amount ofdimethylformamide.

Process variant (B) is typically carried out in an aprotic solvent suchas dichloromethane or dichloroethane in the presence of anon-interfering base such as triethylamine. The reaction may beconducted at room temperature.

Intermediate compounds of the formula (10) can be prepared by the seriesof reactions shown in Scheme 1 below.

In reaction Scheme 1, the piperidine carboxylic acid (12) is reactedwith the substituted ketone (13) under reductive amination conditions.The reductive amination reaction is typically carried out with mildheating (e.g. to a temperature of from about 40° C. to about 70° C.)using a borohydride reducing agent such as sodium triacetoxyborohydridein a solvent such as dichloromethane or dichloroethane containing aceticacid. In an alternative sequence of reactions, an ester (e.g. the ethylester) of the piperidine carboxylic acid (12) is reacted with thepiperidone (13) in the presence of either sodium cyanoborohydride incombination with zinc chloride or sodium triacetoxyborohydride incombination with titanium isopropoxide to give an intermediate estercompound (not shown) which is then selectively hydrolysed under mildconditions using lithium hydroxide or sodium hydroxide to give compound(10). Compounds of the formula (11) can be prepared by the sequence ofreactions shown in Scheme 2 below.

In Scheme 2, the piperidine ester (14, R″=ethyl) is reacted with theketone (15) under reductive amination conditions of the type describedabove to give an intermediate ester (not shown) which is thenselectively hydrolysed using lithium hydroxide to give the carboxylicacid (16). The carboxylic acid (16) is then reacted with an amine HNR¹R²under amide-forming conditions (see above) to give an intermediate amidecompound (not shown) which is then deprotected by removal of the Bocgroup by treatment with acid (e.g. trifluoroacetic acid indichloromethane) to give the compound (11).

In formula (1) and the formulae shown in the reaction Schemes 1 and 2above, when “n” is 2, the right hand heterocyclic ring is an azepinering and a chiral centre can exist at the carbon atom of the azepinering which is attached to the piperidine ring. Although individualoptical isomers can be isolated and purified by standard methods at theend of the reaction sequence, it is also possible to prepare compoundsof the formula (1) wherein n is 2 having a desired stereochemistry atthe chiral carbon atom by using chiral intermediates of the formula(16).

A synthetic route which provides chiral intermediate compounds of theformula (16) wherein n is 2 and R⁵ is absent, is set out in Scheme 3below.

The starting material for the reaction sequence shown in Scheme 3 is theprotected (4S)-4-aminoazepine derivative (17) in which the ring nitrogenof the azepine is protected by a Boc group and the 4-amino moiety isprotected as a (1R)-1-phenethylamino group. The first step of thereaction sequence involves the removal of the phenethylamine protectinggroup using palladium hydroxide on carbon and ammonium formate inmethanol with heating to give the 4-aminoazepine (18). The4-aminoazepine (18) is then reacted with the dialdehyde (20) (which canbe generated in situ by subjecting methyl cyclopent-3-ene-1-carboxylateto ozonolysis) under reductive amination conditions as described above(e.g. using sodium triacetoxyborohydride) to give thepiperidinyl-azepine (21). Hydrolysis of the piperidine carboxylic estergroup using sodium hydroxide gives the (S) optical isomer of theN-protected-azepinyl-piperidinyl carboxylic acid (16).

In order to give the corresponding (R) optical isomer of compound (16),the corresponding (4R)-4-aminoazepine isomer of compound (17) can beused as the starting material.

Once formed, one compound of the formula (1), or a protected derivativethereof, can be converted into another compound of the formula (1) bymethods well known to the skilled person. Examples of syntheticprocedures for converting one functional group into another functionalgroup are set out in standard texts such as Advanced Organic Chemistryand Organic Syntheses (see references above) or Fiesers' Reagents forOrganic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser(ISBN: 0-471-58283-2).

In many of the reactions described above, it may be necessary to protectone or more groups to prevent reaction from taking place at anundesirable location on the molecule. Examples of protecting groups, andmethods of protecting and deprotecting functional groups, can be foundin Protective Groups in Organic Synthesis (T. Greene and P. Wuts; 3rdEdition; John Wiley and Sons, 1999).

Compounds made by the foregoing methods may be isolated and purified byany of a variety of methods well known to those skilled in the art andexamples of such methods include recrystallisation and chromatographictechniques such as column chromatography (e.g. flash chromatography) andHPLC.

Pharmaceutical Formulations

While it is possible for the active compound to be administered alone,it is preferable to present it as a pharmaceutical composition (e.g.formulation).

Accordingly, in another embodiment (Embodiment 4.1) of the invention,there is provided a pharmaceutical composition comprising at least onecompound of the formula (1) as defined in any one of Embodiments 1.1 to1.70 together with at least one pharmaceutically acceptable excipient.

In one embodiment (Embodiment 4.2), the composition is a tabletcomposition.

In another embodiment (Embodiment 4.3), the composition is a capsulecomposition. The pharmaceutically acceptable excipient(s) can beselected from, for example, carriers (e.g. a solid, liquid or semi-solidcarrier), adjuvants, diluents (e.g solid diluents such as fillers orbulking agents; and liquid diluents such as solvents and co-solvents),granulating agents, binders, flow aids, coating agents,release-controlling agents (e.g. release retarding or delaying polymersor waxes), binding agents, disintegrants, buffering agents, lubricants,preservatives, anti-fungal and antibacterial agents, antioxidants,buffering agents, tonicity-adjusting agents, thickening agents,flavouring agents, sweeteners, pigments, plasticizers, taste maskingagents, stabilisers or any other excipients conventionally used inpharmaceutical compositions.

The term “pharmaceutically acceptable” as used herein means compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof a subject (e.g. a human subject) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each excipient mustalso be “acceptable” in the sense of being compatible with the otheringredients of the formulation.

Pharmaceutical compositions containing compounds of the formula (1) canbe formulated in accordance with known techniques, see for example,Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton,Pa., USA.

The pharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, intrabronchial, sublingual, ophthalmic,otic, rectal, intra-vaginal, or transdermal administration.

Pharmaceutical dosage forms suitable for oral administration includetablets (coated or uncoated), capsules (hard or soft shell), caplets,pills, lozenges, syrups, solutions, powders, granules, elixirs andsuspensions, sublingual tablets, wafers or patches such as buccalpatches.

Tablet compositions can contain a unit dosage of active compoundtogether with an inert diluent or carrier such as a sugar or sugaralcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugarderived diluent such as sodium carbonate, calcium phosphate, calciumcarbonate, or a cellulose or derivative thereof such as microcrystallinecellulose (MCC), methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, and starches such as corn starch. Tablets may also containsuch standard ingredients as binding and granulating agents such aspolyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymerssuch as crosslinked carboxymethylcellulose), lubricating agents (e.g.stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT),buffering agents (for example phosphate or citrate buffers), andeffervescent agents such as citrate/bicarbonate mixtures. Suchexcipients are well known and do not need to be discussed in detailhere.

Tablets may be designed to release the drug either upon contact withstomach fluids (immediate release tablets) or to release in a controlledmanner (controlled release tablets) over a prolonged period of time orwith a specific region of the GI tract.

The pharmaceutical compositions typically comprise from approximately 1%(w/w) to approximately 95%, preferably % (w/w) active ingredient andfrom 99% (w/w) to 5% (w/w) of a pharmaceutically acceptable excipient(for example as defined above) or combination of such excipients.Preferably, the compositions comprise from approximately 20% (w/w) toapproximately 90% (w/w) active ingredient and from 80% (w/w) to 10% of apharmaceutically excipient or combination of excipients. Thepharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, pre-filled syringes, dragées, powders,tablets or capsules.

Tablets and capsules may contain, for example, 0-20% disintegrants, 0-5%lubricants, 0-5% flow aids and/or 0-99% (w/w) fillers/or bulking agents(depending on drug dose). They may also contain 0-10% (w/w) polymerbinders, 0-5% (w/w) antioxidants, 0-5% (w/w) pigments. Slow releasetablets would in addition typically contain 0-99% (w/w)release-controlling (e.g. delaying) polymers (depending on dose). Thefilm coats of the tablet or capsule typically contain 0-10% (w/w)polymers, 0-3% (w/w) pigments, and/or 0-2% (w/w) plasticizers.

Parenteral formulations typically contain 0-20% (w/w) buffers, 0-50%(w/w) cosolvents, and/or 0-99% (w/w) Water for Injection (WFI)(depending on dose and if freeze dried). Formulations for intramusculardepots may also contain 0-99% (w/w) oils.

The pharmaceutical formulations may be presented to a patient in“patient packs” containing an entire course of treatment in a singlepackage, usually a blister pack.

The compounds of the formula (1) will generally be presented in unitdosage form and, as such, will typically contain sufficient compound toprovide a desired level of biological activity. For example, aformulation may contain from 1 nanogram to 2 grams of active ingredient,e.g. from 1 nanogram to 2 milligrams of active ingredient. Within theseranges, particular sub-ranges of compound are 0.1 milligrams to 2 gramsof active ingredient (more usually from 10 milligrams to 1 gram, e.g. 50milligrams to 500 milligrams), or 1 microgram to 20 milligrams (forexample 1 microgram to 10 milligrams, e.g. 01 milligrams to 2 milligramsof active ingredient).

For oral compositions, a unit dosage form may contain from 1 milligramto 2 grams, more typically 10 milligrams to 1 gram, for example 50milligrams to 1 gram, e.g. 100 milligrams to 1 gram, of active compound.

The active compound will be administered to a patient in need thereof(for example a human or animal patient) in an amount sufficient toachieve the desired therapeutic effect (effective amount). The preciseamounts of compound administered may be determined by a supervisingphysician in accordance with standard procedures.

EXAMPLES

The invention will now be illustrated, but not limited, by reference tothe specific embodiments described in the following examples.

Examples 1 to 82

The compounds of Examples 1 to 82 shown in Table 1 below have beenprepared. Their NMR and LCMS properties and the methods used to preparethem are set out in Table 2.

TABLE 1

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

Example 51

Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Example 58

Example 59

Example 60

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 74

Example 75

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

Example 82

General Procedures

Where no preparative routes are included, the relevant intermediate iscommercially available. Commercial reagents were utilized withoutfurther purification. Room temperature (rt) refers to approximately20-27° C. ¹H NMR spectra were recorded at 400 MHz on either a Bruker orJeol instrument. Chemical shift values are expressed in parts permillion (ppm), i.e. (δ)-values. The following abbreviations are used forthe multiplicity of the NMR signals: s=singlet, br=broad, d=doublet,t=triplet, q=quartet, quint=quintet, td=triplet of doublets, tt=tripletof triplets, qd=quartet of doublets, ddd=doublet of doublet of doublets,ddt=doublet of doublet of triplets, m=multiplet. Coupling constants arelisted as J values, measured in Hz. NMR and mass spectroscopy resultswere corrected to account for background peaks. Chromatography refers tocolumn chromatography performed using 60-120 mesh silica gel andexecuted under nitrogen pressure (flash chromatography) conditions. TLCfor monitoring reactions refers to TLC run using the specified mobilephase and the silica gel F254 as a stationary phase from Merck.Microwave-mediated reactions were performed in Biotage Initiator or CEMDiscover microwave reactors.

Mass spectroscopy was carried out on Shimadzu LC-2010 EV, WatersZQ-2000, UPLC-Mass SQD-3100 or Applied Biosystem API-2000 spectrometersusing electrospray conditions as specified for each compound in thedetailed experimental section.

Preparative HPLC was typically carried out under the followingconditions, (Waters HPLC): Column: XSelect CSH Prep C-18, 19×50 mm, 5μm; Mobile phase: Gradients of water and MeCN (each containing 0.1%Formic Acid); gradient 5% MeCN in 0.1 HCOOH in water (30 sec), 5% to 40%(over 7 min) then 95% MeCN in 0.1 HCOOH in water (1 min) then 5% MeCN in0.1 HCOOH in water (1.5 min) at 28 mL/min.

LCMS experiments were typically carried out using electrosprayconditions as specified for each compound under the followingconditions:

Method A and B

Instruments: Waters Alliance 2795, Waters 2996 PDA detector, MicromassZQ; Column: Waters X-Bridge C-18, 2.5 micron, 2.1×20 mm or PhenomenexGemini-NX C-18, 3 micron, 2.0×30 mm; radient [time (min)/solvent D in C(%)]: Method A: 0.00/2, 0.10/2, 2.50/95, 3.50/95, 3.55/2, 4.00/2 orMethod B: 0.00/2, 0.10/2, 8.40/95, 940/95, 9.5012, 10.00/2; Solvents:solvent C=2.5 L H₂O+2.5 mL ammonia solution; solvent D=2.5 L MeCN+135 mLH₂O+2.5 mL ammonia solution); Injection volume 3 uL; UV detection 230 to400 nM; column temperature 45° C.; Flow rate 1.5 mL/min.

Method C

Instrument: Agilent 1200 LCMS. Column: Agilent Zorbax Extend RRHT, 1.8μm, 4.6×30 mm. Detection wavelength: 254 nm. Gradient [time(min)/solvent B in A (%), flow rate]: 0.00/5 (2.5 mL/min), 3.00/95 (2.5mL/min), 3.01/95 (4.5 mL/min), 3.50/95 (4.5 mL/min), 3.60/5 (3.5mL/min), 3.90195 (3.5 mL/min), 4.00/5 (2.5 mL/min) (solvent A: waterwith 0.1% formic acid; solvent B: MeCN with 0.1% formic acid).

Method D

Instrument: LCMS (Agilent 1200-6110) with UV and ELSD detector at 40° C.using waters X-Bridge C18 (4.6 mm*50 mm, 3.5 urn) and using water (0.05%TFA) and acetonitrile (0.05% TFA) as the mobile phase. The eluentgradient program was MECN (0.05% TFA) from 5% to 100% for 1.6 min and100% MECN (0.05% TFA) for 1.4 min. The flow rate was 2.0 mL/min.

Method E

Instrument: LCMS (Agilent 1200-6110) with UV and ELSD detector at 40° C.using waters X-Bridge C18 (4.6 mm*50 mm, 3.5 um) and using water (0.05%TFA) and acetonitrile (0.05% TFA) as the mobile phase. The eluentgradient program was MECN (0.05% TFA) from 5% to 100% for 5 min and 100%MeCN (0.05% TFA) for 1.0 min. The flow rate was 2.0 mL/min.

LCMS data in the experimental section are given in the format: Mass ion,retention time, approximate purity.

Abbreviations

-   d=day(s)-   DCE=dichloroethane-   DCM=dichloromethane-   DMF=dimethylformamide-   DMSO=dimethylsulfoxide-   ESI electro spray ionisation-   EtOAc=ethyl acetate-   h=hour(s)-   HATU 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HPLC=high performance liquid chromatography-   LC=liquid chromatography-   MeCN=acetonitrile-   min=minute(s)-   MS=mass spectrometry-   NMR=nuclear magnetic resonance-   rt=room temperature-   sat.=saturated-   sol.=solution-   STAB=sodium triacetoxyborohydride-   THF=tetrahydrofuran-   TLC=thin layer chromatography

Prefixes n-, s-, i-, t- and tert- have their usual meanings: normal,secondary, iso, and tertiary.

SYNTHESIS OF INTERMEDIATES Intermediate 1 Preparation of1′-(ethoxycarbonyl)-1,4′-bipiperidine-4-carboxylic Acid

A solution of Isonipecotic acid (8.0 g, 61.0 mmol) in DCE (80 mL) wastreated with acetic acid (10.7 mL, 185 mmol) and1-carbethoxy-4-piperidone (12.7 g, 74.3 mmol). The reaction mixture wasstirred for 1 hr at 40° C. Then STAB (29.2 g, 92.8 mmol) was added, thereaction mixture was stirred at 70° C. for 6 h, cooled to rt and thesolvent was removed in vacuo. The residue was purified by columnchromatography (gradient 0% to 50% MeOH in CHCl₃) to give1′-(ethoxycarbonyl)-1,4′-bipiperidine-4-carboxylic acid (16.0 g, 92.2%),Intermediate 1, as an off white solid.

Mass spectroscopy: (ESI+ve) 285.1 [M+H]⁺.

¹H NMR: (400 MHz, CD₃OD) δ: 1.26 (t, J=7.1, 3H), 1.61 (qd, J=12.3, 8.0,2H), 1.83-2.17 (m, 5H), 2.32-2.44 (m, 1H), 2.75-3.14 (m, 4H), 3.23-3.28(m, 2H), 3.35-3.50 (m, 2H), 4.12 (q, J=7.1, 2H), 4.26-4.30 (m, 2H), OHproton not observed.

Intermediate 2 Preparation of1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic Acid

Ethyl isonipecotate (2.54 g, 2.50 mL, 16.2 mmol) and4-oxoazepane-1-carboxylic acid ethyl ester (3.00 g, 16.2 mmol) weredissolved in DCM (100 mL) at rt and titanium isopropoxide (5.07 g, 5.40mL, 17.8 mmol) was added. The reaction mixture was stirred at rt for 1h. STAB (13.7 g, 32.4 mmol) and acetic acid (0.5 mL) were added and thereaction mixture was stirred at rt overnight under nitrogen. Thereaction mixture was quenched with the addition of water (5 mL) andstirred for 5 minutes. The reaction mixture was diluted with DCM andfiltered through a pad of celite. The filtrate was washed with sat.NaHCO₃ sol., sat. NaCl sol and dried over MgSO₄. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 urn, 60 Å, 50mL per min, gradient 2% to 4% MeOH in DCM]) to give ethyl4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.56 g, 48%)as a pale yellow oil.

LCMS (Method A): m/z 327 (M+H)⁺ (ES⁺), at 1.68 min, UV inactive

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.17 (t, J=7.0, 6H), 1.49-1.55 (m, 6H),1.75-1.78 (m, 5H), 2.14-2.23 (m, 1H), 2.37 (t, J=9.1, 1H), 2.64-2.72 (m,2H), 3.18-3.24 (m, 2H), 3.41-3.44 (m, 2H), 3.61-3.70 (m, 1H), 3.99-4.08(in, 4H)

Ethyl 4-[4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (1.10 g,3.4 mmol) was dissolved in THF (60 mL) at rt and 1M LiOH sol. (10 mL)was added. The reaction mixture was stirred at rt for 5d. The pH wascarefully adjusted to pH 6 by addition of concentrated hydrochloricacid, the solvents were removed in vacuo, to give1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (1.5 g) asa viscous pale yellow oil, Intermediate 2, which was used crude insubsequent reactions.

LCMS (Method A): m/z 299 (M+H)⁺ (ES⁺), at 0.12 min, UV inactive

¹H NMR: (400 MHz, CD₃OD) δ: 1.22-1.32 (m, 3H), 1.60-2.38 (m, 11H),2.08-2.22 (m, 1H), 3.13-3.26 (m, 2H), 3.33-3.51 (m, 2H), 3.52-3.76 (m,2H), 4.08-4.18 (m, 2H), OH proton not observed.

Intermediate 3 Preparation of1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic Acid

Ethyl 4-fluoropiperidine-4-carboxylate hydrochloride (3.00 g, 14.2 mmol)was dissolved in methanol (20 mL) and treated with K₂CO₃ (1.95 g, 14.2mmol) in a minimum of water to de-salt. Reaction mixture wasconcentrated in vacuo and azeotroped to dryness with toluene. Theresidue and 4-oxoazepane-1-carboxylic acid ethyl ester (2.62 g, 14.2mmol) were dissolved in methanol (50 mL) and zinc chloride (7.23 g, 56.7mmol) was added. The reaction mixture was stirred at 50° C., under anitrogen atmosphere, for 2 h then cooled to rt. NaCNBH₄ (1.78 g, 28.4mmol) was added and the reaction mixture was stirred at 50° C. overnightunder nitrogen. The reaction mixture was cooled to rt and the solventswere removed in vacuo, the residue was diluted with DCM and treated withsat. NaHCO₃ sol., the resulting heterogeneous mixture was filteredthrough a celite pad and the filtrate was washed with sat. NaHCO₃ sol.,sat. NaCl sol. and dried over MgSO₄. The solvents were removed in vacuo,and the residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min,gradient 0% to 4% MeOH in DCM]) to give ethyl4-[4-fluoro-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.26g, 46%) as a colourless oil.

LCMS (Method A): m/z 331 (M+H)⁺ (ES⁺), at 1.84 min, UV inactive

¹H NMR: (400 MHz, CDCl₃) δ: 1.24-1.31 (m, 6H), 1.43-1.59 (m, 2H),1.61-1.69 (m, 2H), 1.86-2.15 (m, 7H), 254-2.67 (m, 4H), 3.32-3.32 (m,2H), 3.48-3.61 (m, 2H), 4.12 (q, J=6.8, 2H), 4.22 (q, J=7.2, 2H)

Ethyl 4-[4-fluoro-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(2.26 g, 6.85 mmol) was dissolved in THF (60 mL) at rt and 1M LiOH sol.(6.5 mL) was added. The reaction mixture was stirred at rt overnight.The pH was carefully adjusted to pH 6 by addition of concentratedhydrochloric acid, the solvents were removed in vacuo, to give1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid(3.21 g) as a white waxy solid, Intermediate 3, which was used crude insubsequent reactions.

LCMS (Method A): m/z 317 (M+H)⁺ (ES⁺), at 0.24 min, UV inactive

Intermediate 4 Preparation of1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methylpiperidine-4-carboxylic Acid

Ethyl-4-methylpiperidine-4-carboxylate hydrochloride (0.50 g, 2.42 mmol)was dissolved in methanol (10 mL) and treated with K₂CO₃ (0.33 g, 2.42mmol) in a minimum of water to de-salt. Reaction mixture wasconcentrated in vacuo and azeotroped to dryness with toluene. Theresidue and 4-oxoazepane-1-carboxylic acid ethyl ester (0.45 g, 2.42mmol) were dissolved in DCM (20 mL) at rt and titanium isopropoxide(0.76 g, 0.8 mL, 2.66 mmcl) was added. The reaction mixture was stirredat rt for 5 h. STAB (2.05 g, 9.66 mmol) and acetic acid (0.3 mL) wereadded and the reaction mixture was stirred at rt overnight undernitrogen. The reaction mixture was quenched with the addition of water(5 mL) and stirred for 5 minutes. The reaction mixture was diluted withDCM and filtered through a pad of celite. The filtrate was washed withsat. NaHCO₃ sol., sat. NaCl sol. and dried over MgSO₄. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.37g, 45.0%) as a pale yellow oil.

LCMS (Method A): m/z 341 (M+H)⁺ (ES⁺), at 1.73 min, UV inactive

¹H NMR: (400 MHz, CDCl₃) δ: 1.16 (s, 3H), 1.23-1.27 (t, J=7.2, 6H),1.40-1.89 (m, 5H), 1.92-1.93 (m, 4H), 2.11-2.62 (m, 6H), 3.25-3.51 (m,4H), 4.09-4.17 (n, 4H).

Ethyl 4-[4-methyl-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0.37 g, 1.09 mmol) was dissolved in THF (10 mL) at rt and 1M LiOH sol.(3.3 mL) was added. The reaction mixture was stirred at rt overnight.The pH was carefully adjusted to pH 6 by addition of concentratedhydrochloric acid, the solvents were removed in vacuo, to give1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methylpiperidine-4-carboxylic acid(0.66 g) as a viscous colourless oil, Intermediate 4, which was usedcrude in subsequent reactions.

LCMS (Method A): m/z 317 (M+H)⁺ (ES⁺), at 0.24 min, UV inactive

Intermediate 5 Preparation of1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA Salt

Ethyl isonipecotate (2.28 g, 2.25 mL, 14.5 mmol) and4-oxoazepane-1-carboxylic acid ter-butyl ester (3.00 g, 14.5 mmol) weredissolved in DCM (60 mL) at rt and titanium isopropoxide (4.12 g, 4.40mL, 14.5 mmol) was added. The reaction mixture was stirred at rt for 1h. STAB (13.74 g, 32.4 mmol) and acetic acid (0.5 mL) were added and thereaction mixture was stirred at rt overnight under nitrogen. Thereaction mixture was quenched with the addition of water (5 mL) andstirred for 5 minutes. The reaction mixture was diluted with DCM andfiltered through a pad of celite. The filtrate was washed with sat.NaHCO₃ sol., sat. NaCl sol. and dried over MgSO₄. The solvents wereremoved in vacuo, and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 50 g, 40-63 urn, 60 Å, 50mL per min, gradient 0% to 4% MeOH in DCM]) to give ethyl4-[4-(tert-butoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (2.61 g,50.8%) as a pale yellow oil.

LCMS (Method A): m/z 355 (M+H)⁺ (ES⁺), at 1.93 min, UV inactive

Ethyl 4-[4-(tert-butoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(261 g, 7.4 mmol) was dissolved in THF (60 mL) at rt and 1M LiOH sol.(10 mL) was added. The reaction mixture was stirred at rt overnight. Thesolvents were removed in vacuo, to give1-(1-(tert-butoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid whichwas used crude is subsequent reaction.

LCMS (Method A): m/z 327 (M+H)⁺ (ES⁺), at 0.15 min, UV inactive

Residue was dissolved in DMF (30 mL) and isobutylamine (0.81 g, 1.1 mL,11.0 mmol), HATU (4.20 g, 11.0 mmol) and DIPEA (4.76 g, 6.41 mL, 36.8mmol) were added. The reaction mixture was stirred at rt for 48 h undernitrogen. The solvents were removed in vacuo, and the residue waspartitioned between DCM and sat. NaHCO₃ sol., organic layer washed withsat. NaCl sol. and dried over MgSO₄. The solvents were removed in vacuo,and the residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 50 g, 40-63 μm, 60 Å, 50 mL per min,gradient 0% to 10% MeOH in DCM]) to give tert-butyl4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate(1.95 g, 69.4%) as a pale yellow oil.

LCMS (Method A): m/z 382 (M+H)⁺ (ES⁺), at 1.76 min, UV inactive

tert-Butyl4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate(1.95 g, 5.1 mmol) was dissolved in DCM (16 mL) and TFA (4 mL) wasadded. The reaction mixture was stirred at rt for 2 h under nitrogen,then the solvents were removed in vacuo, to give1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt(2.02 g), Intermediate 5, as a dark yellow oil which was used directlywithout further purification.

LCMS (Method A): m/z 282 (M+H)⁺ (ES⁺), at 1.34 min, UV inactive

Intermediate 6-(R) and 6-(S

A mixture of 4-oxoazepane-1-carboxylic acid tert-butyl ester (90 g, 422mmol) and (R)-1-phenylethanamine (56.4 g, 465 mmol) in THF (1000 mL) wasstirred at rt for 15 min and STAB (107.4 g, 510 mmol) was added. Themixture was cooled to 0° C. in an ice bath, then acetic acid (26.7 g,450 mmol) was added. The mixture was stirred overnight at rt thenconcentrated in vacuo, residue dissolved in DCM (800 mL) and washed withsat. NaHCO₃ sol. (2×300 mL), dried (Na₂SO₄). The solvents were removedin vacuo, and the residue was purified by column chromatography(gradient 0% to 3% MeOH in DCM) to give tert-butyl4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (90 g, 67.0%) as amixture of two diastereoisomers.

LCMS (Method D): m/z 319 (M+H)⁺ (ES⁺), at 1.25 min, 95%

70 g of this mixture was separated by chiral prep. HPLC [Instrument:Waters Thar-SFC 200 with UV detector GILSON UV-1(−151/152/155/156) at35° C. using CHIRALPAK AY-H (2.0 cm I.D.×25 cm L. 5 um) and using(Acetonitrile/iso-propanol)(0.2% DEA)/CO2=1.2/4.8194 (V/VV) as themobile phase. Flow rate was 120 mL/min (all solvents were HPLC grade).The system back pressure was 100 bar. The SFC system was monitored at214 nm.] to afford tert-butyl(4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (26 g, 24.9%yield) as a yellow oil and tert-butyl(4R)-4-{[(1R-1-phenylethyl]amino}azepane-1-carboxylate (30 g, 28.6%yield) as a yellow oil.

tert-butyl (4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate

¹H NMR: (400 MHz, CDCl₃) δ: 1.26 (d, J=7.1, 3H), 1.33 (s, 9H), 1.34-1.43(m, 3H), 1.72-1.97 (m, 3H), 2.34-2.39 (m, 1H), 3.01-3.45 (m, 4H), 380(q, J=7.2, 1H), 7.15-7.25 (in. 5H), NH proton not observed

[α]_(D) ²⁰=+57.0 (c=0.5 in MeOH)

The absolute configuration was determined by X-ray analysis of thep-bromobenzoate salt of tert-butyl(4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate. (A. Alker etal, Bioorg. Med. Chem. Lett. 20 (2010) 4521-4525)

tert-butyl (4R)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate

¹H NMR: (400 MHz, CDCl₃) δ: 1.27 (d, J=7.0, 3H), 1.34 (s, 9H), 1.34-1.42(m, 3H), 1.74-1.96 (m, 3H), 2.35-2.41 (m, 1H), 3.02-3.45 (m, 4H), 3.81(q, J=7.1, 1H), 7.16-7.26 (m, 5H), NH proton not observed

[α]_(D) ²⁰=−31.8 (c=0.5 in MeOH)

Intermediate 6-(S) Preparation of Tert-Butyl(4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate

A suspension of Pd(OH)₂/C (10%, 550 mg), tert-butyl(4S)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (5.5 g, 17.3mmol) and HCOONH₄ (3.3 g, 51.9 mmol) in MeOH (80 mL) was heated atreflux for 1.5 h. The reaction mixture was cooled to rt and filtered,the solvents of the filtrate were removed in vacuo. The residue waspurified by column chromatography (gradient 0% to 10% MeOH in DCM) togive tert-butyl (4S)-4-aminoazepane-1-carboxylate (3.2 g, 87.3%).

LCMS (Method E): m/z 215 (M+H)⁺ (ES⁺), at 1.53 min, UV inactive

¹H NMR: (400 MHz, CDCl₂) δ: 1.34-1.42 (m, 3H), 1.39 (s, 9H), 1.45-1.53(m, 2H), 1.60-1.86 (m, 3H), 2.80-2.90 (m, 1H), 3.08-3.53 (m, 4H)

[α]_(D) ²⁰=+21.3 (c=1.0 in MeOH)

Methyl cyclopent-3-ene-1-carboxylate (4.42 g, 35 mmol) was dissolved inDCM/MeOH (160 mL, 3:1) and cooled to −78° C. Ozone was passed throughthe solution until a blue colour persisted. Excess ozone was purged fromthe reaction mixture with dry N₂. Dimethylsulfide (10 mL) was added andthe reaction mixture was warmed to rt, the solvent was removed in vacuo.The residue was added to a solution of tert-butyl(4S)-4-aminoazepane-1-carboxylate (7.5 g, 35 mmol), STAB (18.57 g, 87.6mmol), NEt₃ (4.26 g, 42.1 mmol) and acetic acid (1.8 mL) in DCE (200mL). The mixture was stirred for 3 hours at rt and was then poured intoaqueous Na₂CO₃ solution. The mixture was extracted with EtOAc (3×200mL), the organic phase were washed with water (100 mL) and brine (100mL), dried over Na₂SO₄. The solvent was removed in vacuo, and theresidue was purified by column chromatography (gradient 0% to 25% EtOAcin Petroleum ether) to give tert-butyl(4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (7.7 g,64.6% yield) as a yellow oil.

LCMS (Method D): m/z 341 (M+H)⁺ (ES⁺), at 1.49 min, UV inactive

tert-Butyl(4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (7.7 g,22.7 mmol) was dissolved in THF and water (60 mL, 1:1) and cooled to 0°C. NaOH (1.0 g, 24.5 mmol) was added and the reaction mixture wasstirred at rt for 3 h. The organics solvents were removed in vacuo, andthe aqueous phase was acidified with acetic acid to pH=3˜4, thenconcentrated to dryness. The residue was suspended in CHCl₃ (40 mL) andfiltered to remove inorganic salts. The filtrate was evaporated todryness to afford1-{(4S)-1-[(tert-butoxycarbonyl)carbonyl]azepan-4-yl}piperidine-4-carboxylicacid (6.2 g, 84% yield) as a yellow oil.

LCMS (Method D): m/z 327 (M+H)⁺ (ES⁺), at 1.35 min, UV inactive

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.38 (s, 9H), 1.45-1.53 (m, 6H), 1.70-1.78(m, 4H), 2.08-2.20 (m, 3H), 2.35-2.42 (m, 1H), 2.65-2.69 (m, 2H),3.12-3.19 (m, 2H), 3.30-3.41 (m, 2H), 8.32 (br. s, 1H)

[α]_(D) ²⁰=+11.0 (c=1.8 in MeOH)

Intermediate 6-R Preparation of Tert-Butyl(4R)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate

The title compound (6.1 g, 18.7 mmol) was prepared from tert-butyl(4R)-4-{[(1R)-1-phenylethyl]amino}azepane-1-carboxylate (5.5 g, 17.3mmol) using the method outlined above for Intermediate 6-(S).

LCMS (Method D): m/z 327 (M+H)⁺ (ES⁺), at 1.35 min, UV inactive

¹H NMR: (400 MHz, DMSO-d₆) δ: 1.39 (s, 9H), 1.45-1.53 (m, 6H), 1.70-1.78(m, 4H), 2.08-2.20 (m, 3H), 2.35-2.41 (m, 1H), 2.64-2.69 (m, 2H),3.12-3.19 (m, 2H), 3.30-3.41 (m, 2H), 8.32 (br. s, 1H)

[α]_(D) ²⁰=−10.7 (c=2.0 in MeOH).

Intermediate 7 Preparation of1-(azepan-4-yl)-4-methoxy-N-(1-methylcyclobutyl)piperidine-4-carboxamideTFA Salt

4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50g, 2.38 mmol) was dissolved in methanol (10 mL) and treated with K₂CO₃(0.328 g, 2.38 mmol) in a minimum of water to de-salt. The reactionmixture was concentrated in vacuo and azeotroped to dryness withtoluene. The residue and 4-oxoazepane-1-carboxylic acid tert-butyl ester(0.745 g, 2.38 mmol) were dissolved in methanol (20 mL) at rt andtreated with zinc chloride (0.975 g, 7.15 mmol). The reaction mixturewas stirred at 50° C. for 3 h. The solution was cooled to roomtemperature, sodium cyanoborohydride (0.299 g, 4.77 mmol) was added andthe reaction mixture was stirred at 50° C. overnight under nitrogen. Thesolvents were removed in vacuo, and the residue was partitioned betweenDCM and sat. NaHCO₃ sol. The aqueous phase was extracted with DCM (2×20mL). The organics were combined, washed with sat. NaCl sol. and dried bypassing through a Biotage Phase Separator cartridge. The solvents wereremoved in vacuo and the residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50mL per min, gradient 1% to 10% MeOH in DCM]) to give tert-butyl4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0.163 g, 15.5%) as a colourless oil.

LCMS (Method A): m/z 371 (M+H)⁺ (ES⁺), at 1.72 min, UV inactive

tert-butyl4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0.06 g, 0.17 mmol) was dissolved in THF (5 mL) at rt and 1M LiOH sol.(0.35 mL) was added. The reaction mixture was stirred at rt for 8 days.The pH was carefully adjusted to pH 6 by addition of concentratedhydrochloric acid, the solvents were removed in vacuo, to give1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylicacid which was used crude in subsequent reaction.

LCMS (Method A): m/z 357 (M+H)⁺ (ES⁺), at 0.24 min, UV inactive

1-[1-(tert-butoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylicacid (0.163 g, 0.44 mmol) was dissolved in DMF (5 mL) and(1-methyl)cyclobutylamine hydrochloride (0.08 g, 0.66 mmol), HATU (0.25g, 0.66 mmol) and DIPEA (0.284 g, 0.38 mL, 2.20 mmol) were added. Thereaction mixture was stirred at rt overnight under nitrogen. Thesolvents were removed in vacuo, and the residue was partitioned betweenDCM and sat, NaHCO₃ sol., organic layer washed with sat. NaCl sol. anddried over MgSO₄. The solvents were removed in vacuo, and the residuewas purified by column chromatography (normal phase, [Biotage SNAPcartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6%MeOH in DCM]) to give tert-butyl4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate(0.025 g, 13.4%) as a pale yellow oil.

LCMS (Method A): m/z 424 (M+H)⁺ (ES⁺), at 1.88 min, UV inactive

tert-butyl4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate(0.25 g, 0.06 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) wasadded. The reaction mixture was stirred at rt overnight under nitrogen,then the solvents were removed in vacuo, to give1-(azepan-4-yl)-4-methoxy-N-(1-methylcyclobutyl)piperidine-4-carboxamideTFA salt (0.26 g), Intermediate 7, as a dark yellow oil which was useddirectly without further purification.

LCMS (Method A): m/z 324 (M+H)⁺ (ES⁺), at 0.18 min, UV inactive

Intermediate 8 Preparation of1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic Acid

4-Methoxypiperidine-4-carboxylic acid methyl ester hydrochloride (0.50g, 2.38 mmol) was dissolved in methanol (10 mL) and treated with K₂CO₃(0.328 g, 2.38 mmol) in a minimum of water to de-salt. Reaction mixturewas concentrated in vacuo and azeotroped to dryness with toluene. Theresidue and 4-oxoazepane-1-carboxylic acid ethyl ester (0.441 g, 2.38mmol) were dissolved in methanol (20 mL) at rt and treated with zincchloride (0.975 g, 7.15 mmol). The reaction mixture was stirred at 50°C. for 2 h. The solution was cooled to room temperature, sodiumcyanoborohydride (0.299 g, 4.77 mmol) was added and the reaction mixturewas stirred at 50° C. overnight under nitrogen. The solvents wereremoved in vacuo, and the residue was suspended between DCM and sat.NaHCO₃ sol. The turbid mixture, was passed through a pad of celite whichwas washed with DCM. The organics layers were combined, washed with sat.NaCl sol. and dried by passing through a Biotage Phase Separatorcartridge. The solvents were removed in vacuo and the residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min, gradient 1% to 6% MeOH inDCM]) to give ethyl4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0.136 g, 16.4%) as a colourless oil.

LCMS (Method A): m/z 343 (M+H)⁺ (ES⁺), at 1.46 min, UV inactive

Ethyl4-[4-methoxy-4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0,136 g, 0.39 mmcl) was dissolved in THF (5 mL) at rt and 1M LiOH sol.(0.4 mL) was added. The reaction mixture was stirred at rt for 2 days.The pH was carefully adjusted to pH 6 by addition of concentratedhydrochloric acid, the solvents were removed in vacuo, to give1-[1-(ethoxycarbonyl)azepan-4-yl]-4-methoxypiperidine-4-carboxylic acid(0.131 g), Intermediate 8, as a yellow oil which was used directlywithout further purification.

LCMS (Method A): m/z 329 (M+H)⁺ (ES⁺), at 0.13 min, UV inactive

Intermediate 9 Preparation of4-cyano-1-[1-(ethoxycarbonyl)azepan-4-yl]piperidine-4-carboxylic Acid

4-cyanopiperidine (0.40 g, 3.62 mmol) was dissolved in MeOH (15 mL),4-oxoazepane-1-carboxylic acid ethyl ester (0.672 g, 3.62 mmol) and zincchloride (1.98 g, 14.48 mmol) were added. The reaction mixture washeated for 2 h at 50° C. The solution was then cooled on ice and treatedportionwise with sodium cyanoborohydride (0.456 g, 7.24 mmol) andreheated to 50° C. overnight. The reaction mixture was concentrated invacuo to a white solid. This was dissolved in sat. NH₄Cl sol. andextracted with EtOAc (3×50 mL). The combined organics were washed withsat. NaCl sol., dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by column chromatography (normal phase,[Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 50 mL per min,gradient 0% to 4% MeOH in DCM]) to give ethyl4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate as an oil (0.090 g,8.9%).

LCMS (Method A): m/z 280 (M+H)⁺ (ES⁺), at 1.67 min, UV inactive

1.0 M Lithium bis(trimethylsilyl)amide (4.48 mL, 7.17 mmol) was added toanhydrous THF (20 mL) under nitrogen and cooled to −78° C. The solutionwas treated drop wise with ethyl4-(4-cyanopiperidin-1-yl)azepane-1-carboxylate (0.400 g, 1.43 mmol) as asolution in anhydrous THF (2 mL). The solution was stirred at −78° C.under nitrogen for 1 h, ethyl chloroformate (0.17 g, 1.57 mmol) wasadded drop wise. The solution was stirred at −78° C. for a further 2 hand then allowed to warm to rt overnight. The reaction mixture wasquenched with the addition of water and the solvents were removed invacuo. The residue was partitioned between DCM and sat, NaHCO₃ sol. Theorganic layer was washed with sat. NaCl sol, and dried by passingthrough a Biotage Phase Separator cartridge. The solvents were removedin vacuo and the residue was purified by column chromatography (normalphase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 50 mL permin, gradient 2% to 4% MeOH in DCM]) to give ethyl4-[4-cyano-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.067g, 12.7%) as an amber oil.

LCMS (Method A): m/z 352 (M+H)⁺ (ES⁺), at 1.70 min, UV inactive

Ethyl 4-[4-cyano-4-(ethoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate(0.067 g, 0.182 mmol) was dissolved in methanol (4 mL) at rt and 1M LiOHsol. (0.2 mL) was added. The reaction mixture was stirred at rt for 1.5h. The pH was carefully adjusted to pH 6 by addition of concentratedhydrochloric acid, the solvents were removed in vacuo, to give4-cyano-1-[1-(ethoxycarbonyl)azepan-4-yl]piperidine-4-carboxylic acid,(0.62 g), Intermediate 9, as a yellow oil which was used directlywithout further purification.

LCMS (Method A): m/z 324 (M+H)⁺ (ES⁺), at 0.10 min, UV inactive

Route a

Typical Procedure for the Preparation of Amides Via Schotten-BaumannReaction, as Exemplified by the Preparation of Example 1, Ethyl4-(2-methylpropyl)-carbamoyl)-1,4′-bipiperidine-1′-carboxylate

1′-(ethoxycarbonyl)-1,4′-bipiperidine-4-carboxylic acid (0.60 g, 2.11mmol) was dissolved in DCM (30 mL) the reaction mixture was cooled to 0°C. and oxalyl chloride (0.27 mL, 3.17 mmol) and DMF (0.1 mL) was added.The solution was stirred at rt for 2 h and then concentrated in vacuo. Aportion of the residue (0.53 mmol) was dissolved in DCM (5 mL) andiso-butylamine (0.06 g, 0.08 mL, 0.79 mmol) and sat. NaHCO₃ sol. (5 ml)were added. The reaction mixture was stirred at rt overnight and thenpartitioned between DCM and sat. NaHCO₃ sol. The organic layer waswashed with sat. NaCl sol. and dried (MgSO₄) and the solvent was removedin vacuo. The residue was purified by trituration from diethyl ether togive ethyl 4-(2-methylpropyl)carbamoyl)-1,4′-bipiperidine-1′-carboxylate(0.01 g, 9%) as a white solid.

Data in Table 2

Route b

Typical Procedure for the Preparation of Amides Via HATU Coupling, asExemplified by the Preparation of Example 6, Ethyl4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate

1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.26 gassumed 0.89 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.81g, 1.1 mL, 11.0 mmol), HATU (0.51 g, 1.34 mmol) and DIPEA (0.46 g, 0.62mL, 3.56 mmol) were added. The reaction mixture was stirred at rtovernight and the solvents were removed in vacuo. The residue waspartitioned between DCM and sat. NaHCO₃ sol., the organic layer waswashed with sat. NaCl sol. and dried (MgSO₄). The solvents were removedin vacuo, and the residue was purified by column chromatography (normalphase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25 mL permin, gradient 0% to 3% MeOH in DCM]) to give ethyl4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate (17mg, 2%) as a pale yellow gum.

Data in Table 2

Examples 7-16, 19 and 20 Purified by Prep HPLC

Route c

Typical Procedure for the Preparation of Amides Via Acid ChlorideCoupling, as Exemplified by the Preparation of Example 27, Ethyl4-(4-((1-methylcyclobutyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate

Thionyl chloride (5 mL) was added to1-(1-(ethoxycarbonyl)azepan-4-yl)piperidine-4-carboxylic acid (0.2 g,assume 0.34 mmol) and the reaction was stirred at 90° C. for 3 h. Thereaction mixture was cooled to rt and concentrated in vacuo. The residuewas dissolved in DCM (5 mL) and (1-methylcyclobutyl)amine.HCl (60.1 mg,0.50 mmol) and DIPEA (0.23 ml, 1.34 mmol) were added, the reactionmixture was stirred at rt for 48 hours. The solvents were removed invacuo, and the residue was purified by prep HPLC, the resulting productwas loaded onto a SCX column (1 g) in 5% AcOH in MeOH. The column waswashed with MeOH and then the product was eluted with 0.7 M ammonia inMeOH to give the titled compound (26 mg, 21%) as a white solid.

An alternate work up procedure would be: the reaction mixture waspartitioned between DCM and sat. NaHCO₃ sol., the organic layer waswashed with sat. NaCl sol. and dried over MgSO₄. The residue waspurified by column chromatography (normal phase, [Biotage SNAP cartridgeKP-sil 25 g, 40-63 μm, 60 Å, 12 mL per min, gradient 0% to 6% MeOH inDCM]) to give titled compound.

Data in Table 2

Route d

Typical Procedure for the Preparation of Amides Via Acid ChlorideCoupling, as Exemplified by the Preparation of Example 43, Ethyl4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate

Thionyl chloride (4 mL) was added to a solution of1-[1-(ethoxycarbonyl)azepan-4-yl]-4-fluoropiperidine-4-carboxylic acid(1.24 g, assume 3.92 mmol) and the reaction was stirred at 90° C. for 3h. The reaction mixture was cooled to rt and concentrated in vacuo. DCM(4 mL) was added to a portion of the residue (0.65 mmol) followed bytert-butylamine (0.14 mL, 1.31 mmol) and DIPEA (0.57 ml, 3.27 mmol), thereaction mixture was stirred at rt for 48 h. The solvents were removedin vacuo, and the residue was partitioned between DCM (50 mL) and sat.NaHCO₃ sol. (25 mL), organic layer washed with sat. NaCl sol. (25 mL)and dried over MgSO₄. The residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 Å, 25mL per min, gradient 0% to 7% MeOH in DCM]) to give ethyl4-(4-fluoro-4-((tert-butyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate(0.11 g, 46.8%) as a yellow oil.

Data in Table 2

Route e

Typical Procedure for the Preparation of Carbamates Via ChloroformateCoupling, as Exemplified by the Preparation of Example 57,Prop-2-yn-1-yl-4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate

1-(azepan-4-yl)-N-(2-methylpropyl)piperidine-4-carboxamide TFA salt(0.15 g, 0.38 mmol) was dissolved in DCM (8 mL) at rt. NEt₃ (0.16 mL,1.14 mmol) and propargyl chloroformate (0.06 mL, 0.57 mmol) were addedand the reaction mixture was stirred at rt for 2 h under nitrogen. Thesolvents were removed in vacuo, and the residue was partitioned betweenDCM and sat. NaHCO₃ sol.), organic layer washed with sat. NaCl sol. anddried over MgSO₄. The residue was purified by column chromatography(normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 Å, 12mL per min, gradient 0% to 10% MeOH in DCM]) to giveprop-2-yn-1-yl-4-(4-((2-methylpropyl)carbamoyl)piperidin-1-yl)azepane-1-carboxylate(0.04 g, 31%) as a yellow gum.

Data in Table 2

Route f

Typical Procedure for the Preparation of Chiral Derivatives, asExemplified by the Preparation of Example 63, Ethyl(4S)-4-[4-((2-methylpropyl)methylcarbamoyl)-piperidin-1-yl]azepane-1-carboxylate

tert-butyl(4S)-4-[4-(methoxycarbonyl)piperidin-1-yl]azepane-1-carboxylate (0.3 g,0.92 mmol) was dissolved in DMF (4 mL) and isobutylamine (0.14 g, 0.18mL, 1.84 mmol), HATU (0.53 g, 1.38 mmol) and DIPEA (0.36 g, 0.48 mL,2.76 mmol) were added. The reaction mixture was stirred at rt for 48 hand the solvents were removed in vacuo. The residue was partitionedbetween DCM and sat. NaHCO₃ sol., the organic layer was washed with sat.NaCl sol. and dried (MgSO₄). The solvents were removed in vacuo, and theresidue was purified by column chromatography (normal phase, [BiotageSNAP cartridge KP-sil 10 g, 40-63 m, 60 Å, 12 mL per min, gradient 0% to10% MeOH in DCM]) to give tert-butyl(4S)-4-[4-((2-methylpropyl)methylcarbamoyl)piperidin-1-yl]azepane-1-carboxylate(0.12 g, 35%) as a pale yellow gum.

LCMS (Method A): m/z 382 (M+H)⁺ (ES⁺), at 1.72 min, UV inactive

1-[(4S)-azepan-4-yl]-N-(2-methylpropyl)piperidine-4-carboxamide

Residue was dissolved in DCM (4 mL) and TFA (1 mL) was added. Thereaction mixture was stirred at rt for 2 h under nitrogen, then thesolvents were removed in vacuo. The residue was dissolved in DCM (8 mL)at rt. NEt₃ (0.13 mL, 0.96 mmol) and ethyl chloroformate (0.05 mL, 0.48mmol) were added and the reaction mixture was stirred at rt overnightunder nitrogen. The solvents were removed in vacuo, and the residue waspartitioned between DCM and sat. NaHCO₃ sol.), organic layer washed withsat. NaCl sol. and dried over MgSO₄. The residue was purified by columnchromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63μm, 60 Å, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give ethyl(4S)-4-[4-((2-methylpropyl)methylcarbamoyl)piperidin-1-yl]azepane-1-carboxylate(0.24 g, 21%) as a yellow gum.

Data in Table 2

TABLE 2 Syn- Inter- thetic LCMS Ex. medi- meth- Meth- No. Name ate od ¹HNMR od LCMS data 1 ethyl 4-(2- 1 a (400 MHz, DMSO-d₆) δ: 0.80 (d, J =6.5, 6H), 1.16 (t, J = 7.0, B m/z 340 (M + H)⁺ methylpropyl)carbamoyl)-3H), 1.25-1.29 (m, 2H), 1.50-1.76 (m, 7H), 1.94-2.20 (m (ES⁺), at 1.211,4′-bipiperidine-1′- 3H), 2.64-2.67 (m, 1H), 2.83 (t, J = 6.3, 3H),3.14-3.18 min, UV inactive carboxylate (m, 1H), 3.28-3.30 (m, 2H),3.93-3.99 (m, 2H), 4.00 (q, J = 7.0, 2H), 7.68 (br. s, 1H) 2 ethyl4-((3,3- 1 a (400 MHz, CDCl₃) δ: 1.26 (t, J = 7.1, 3H), 1.38-1.50 (m, Bm/z 374 (M + H)⁺ difluoropyrrolidin-1- 1H), 1.63-1.89 (m, 5H), 2.15-2.51(m, 9H), 2.65-2.78 (ES⁺), at 3.91 yl)carbamoyl)-1,4′- (m, 2H), 2.91-3.05(m, 2H), 3.68-3.83 (m, 5H), 4.12 (q, J = min, UV inactivebipiperidine-1′-carboxylate 7.2, 2H) 3 ethyl 4-(2,3-dimethylbutan- 1 a(400 MHz, DMSO-d₆) δ: 0.75 (d, J = 6.8, 6H), 1.09 (s, 6H), B m/z 368(M + H)⁺ 2-yl)carbamoyl)-1,4′- 1.13 (d, J = 7.2, 3H), 1.21-2.32 (m,12H), 2.69-3.10 (m, (ES⁺), at 3.78 bipiperidine-1′-carboxylate 5H),3.94-4.01 (m, 4H), 7.09 (br. s, 1H) min, UV inactive 4 ethyl 4-(1,1- 1 a(400 MHz, DMSO-d₆) δ: 0.69 (t, J = 7.1, 3H), 1.12-1.15 (m, B m/z 354(M + H)⁺ dimethylpropyl)carbamoyl)- 9H), 1.26-2.36 (m, 13H), 2.60-2.93(m, 5H), 3.94-4.01 (ES⁺), at 3.46 1,4′-bipiperidine-1′- (m 4H), 7.07(br. s, 1H) min, UV inactive carboxylate 5 ethyl 4-(1- 1 a (400 MHz,DMSO-d₆) δ: 1.13 (t, J = 7.1, 3H), 1.28 (s, 3H), B m/z 352 (M + H)⁺methylcyclobutyl)carbam- 1.20-2.30 (m, 17H), 2.69-2.85 (m, 5H),3.94-4.01 (m (ES⁺), at 3.14 oyl)-1,4′-bipiperidine-1′- 4H), 7.66 (br. s,1H) min, UV inactive carboxylate 6 ethyl 4-(4-((2- 2 b (400 MHz,DMSO-d₆) δ: 0.92 (d, J = 6.5, 6H), 1.20 (m, 3H), B m/z 354 (M + H)⁺methylpropyl)carbamoyl)pi- 1.25-2.05 (m, 14H), 2.55-2.88 (m, 3H),2.80-2.90 (m, (ES⁺), at 2.90 peridin-1-yl)azepane-1- 2H), 3.20-3.29 (m,2H), 3.40-3.48 (m, 2H), 4.02-4.07 min, UV inactive carboxylate (m, 2H),7.96 (br. s, 1H) 7 ethyl 4-(4-((1,1- 2 b (400 MHz, DMSO-d₆) δ: 1.17 (td,J = 7.1, 2.1, 3H), 1.22 (s, C m/z 354 (M + H)⁺dimethylethyl)carbamoyl)pi- 9H), 1.30-1.56 (m, 7H), 1.68-1.83 (m, 3H),1.93-2.16 (ES⁺), at 2.88 peridin-1-yl)azepane-1- (m, 3H), 2.34-2.40 (m,1H), 2.68-2.75 (m, 2H), 3.12- min, UV inactive carboxylate 3.27 (m, 2H),3.38-3.47 (m, 2H), 4.02 (qd, J = 7.0, 3.2, 2H), 7.26 (br. s, 1H) 8 ethyl4-(4-((2- 2 b (400 MHz, DMSO-d₆) δ: 0.79 (d, J = 6.6, 3H), 0.83 (t, J =7.4, C m/z 368 (M + H)⁺ methylbutyl)carbamoyl)pi- 3H), 0.95-1.08 (m,1H), 1.17 (td, J = 7.0, 2.0, 3H), 1.27- (ES⁺), at 3.07peridin-1-yl)azepane-1- 1.62 (m, 8H), 1.68-1.85 (m, 3H), 2.07-2.17 (m,3H), 2.32- min, UV inactive carboxylate 2.42 (m, 1H), 2.68-2.76 (m, 2H),2.77-2.87 (m, 1H), 2.88- 2.99 (m, 2H), 3.15-3.28 (m, 2H), 3.44-3.51 (m,2H), 4.02 (qd, J = 7.1, 3.0, 2H), 7.67 (t, J = 6.1, 1H) 9 ethyl4-(4-((2,2- 2 b (400 MHz, DMSO-d₆) δ: 0.81 (s, 9H), 1.17 (td, J = 7.0,2.3, C m/z 368 (M + H)⁺ dimethylpropyl)carbamoyl) 3H), 1.30-1.65 (m,6H), 1.70-1.85 (m, 3H), 2.05-2.21 (m, (ES⁺), at 1.82piperidin-1-yl)azepane-1- 3H), 2.32-2.46 (m, 1H), 2.65-2.79 (m, 2H),2.82-3.03 min, UV inactive carboxylate (m, 3H), 3.12-3.27 (m, 2H),3.44-3.49 (m, 2H), 4.07 (qd, J = 7.0, 3.0, 2H), 7.63 (t, J = 6.2, 1H) 10ethyl 4-(4-((1,1- 2 b (400 MHz, DMSO-d₆) δ: 0.72 (t, J = 7.4, 3H),1.10-1.22 (m, C m/z 368 (M + H)⁺ dimethylpropyl)carbamoyl) 9H),1.30-1.65 (m, 9H), 1.70-1.85 (m, 3H), 2.00-2.19 (ES⁺), at 1.87piperidin-1-yl)azepane-1- (m, 3H), 2.32-2.46 (m, 1H), 2.65-2.76 (m, 2H),3.12-3.27 min, UV inactive carboxylate (m, 2H), 3.39-3.48 (m, 2H), 4.02(qd, J = 6.9, 3.1, 2H), 7.11 (br. s, 1H) 11 ethyl 4-(4- 2 b (400 MHz,DMSO-d₆) δ: 1.18 (t, J = 6.8, 3H), 1.30-1.68 (m, C m/z 366 (M + H)⁺((cyclobutylmethyl)carbam- 8H), 1.70-1.86 (m, 5H), 1.89-2.18 (m, 5H),2.32-2.46 (ES⁺), at 1.77 oyl)piperidin-1-yl)azepane-1- (m, 3H),2.67-2.76 (m, 2H), 3.02-3.09 (m, 2H), 3.16-3.23 min, UV inactivecarboxylate (m, 2H), 3.40-3.50 (m, 2H), 4.03 (q, J = 6.9, 2H), 7.62 (br.s, 1H) 12 ethyl 4-(4- 2 b (400 MHz, DMSO-d₆) δ: 0.98 (t, J = 7.0, 3H),1.10 (t, J = 7.0, C m/z 354 (M + H)⁺ ((diethyl)carbamoyl)piperidin- 3H),1.17 (td, J = 7.0, 2.0, 3H), 1.30-1.65 (m, 7H), 1.70- (ES⁺), at 1.8881-yl)azepane-1- 1.85 (m, 3H), 2.17-2.22 (m, 2H), 2.37-2.45 (m, 2H),2.67- min, UV inactive carboxylate 2.78 (m, 2H), 3.16-3.29 (m, 6H),3.41-3.45 (m, 2H), 4.02 (dq, J = 7.0, 2.2, 2H) 13 ethyl4-(4-((ethyl(propan-2- 2 b (400 MHz, DMSO-d₆) δ: 1.00 (t, J = 6.9, 3H),1.05 (d, J = 6.8, C m/z 368 (M + H)⁺ yl)carbamoyl)piperidin-1- 3H),1.10-1.20 (m, 6H), 1.27-1.48 (m, 2H), 1.48-1.65 (ES⁺), at 3.56yl)azepane-1-carboxylate (m, 5H), 1.70-1.86 (m, 3H), 2.14-2.28 (m, 2H),2.30- min, UV inactive 2.42 (m, 2H), 2.65-2.77 (m, 2H), 3.09-3.28 (m,4H), 3.40- 3.49 (m, 2H), 4.03 (qd, J = 7.0, 2.0, 2H), 4.10 (quint., J =6.8, 0.5H), 4.50 (quint., J = 6.8, 0.5H) 14 ethyl 4-(4-((3-methoxy-2- 2b (400 MHz, CDCl₃) δ: 0.90 (d, J = 7.0, 3H), 1.26 (td, J = 7.1, C m/z384 (M + H)⁺ methylpropyl)carbamoyl)pi- 2.3, 3H), 1.39-1.72 (m, 5H),1.75-2.00 (m, 6H), 2.01- (ES⁺), at 1.73 peridin-1-yl)azepane-1- 2.09 (m,1H), 2.15-2.34 (m, 2H), 2.44-2.52 (m, 1H), 2.74- min, UV inactivecarboxylate 2.89 (m, 2H), 3.06 (ddd, J = 13.2, 8.4, 4.3, 1H), 3.19-3.32(m, 3H), 3.35 (s, 3H), 3.38-3.55 (m, 3H), 3.56-3.66 (m, 1H), 4.13 (qd, J= 7.0, 1.6, 2H), 6.32 (br. s, 1H) 15 ethyl 4-(4- 2 b (400 MHz, CDCl₃) δ:0.17-0.23 (m, 2H), 0.47-0.52 (m, C m/z 352 (M + H)⁺((cyclopropylmethyl)carbam- 2H), 0.88-0.97 (m, 1H), 1.26 (td, J = 7.1,2.1, 3H), 1.35- (ES⁺), at 1.71 oyl)piperidin-1- 1.78 (m, 5H), 1.80-2.15(m, 6H), 2.18-2.35 (m, 2H), 2.44- min, UV inactiveyl)azepane-1-carboxylate 2.53 (m, 1H), 2.75-2.90 (m, 2H), 3.08-3.13 (m,2H), 3.22-3.32 (m, 2H), 3.48-3.63 (m, 2H), 4.10-4.16 (m, 2H), 5.64 (br.s, 1H) 16 ethyl 4-(4- 2 b (400 MHz, CDCl₃) δ: 1.13-1.21 (m, 2H), 1.26(td, J = 7.1, C m/z 380 (M + H)⁺ ((cyclopentylmethyl)carbam- 2.0, 3H),1.36-2.50 (m, 21H), 2.75-2.92 (m, 2H), 3.15- (ES⁺), at 2.03oyl)piperidin-1-yl)azepane- 3.35 (m, 4H), 3.45-3.65 (m, 2H), 4.10-4.18(m, 2H), 5.55 min, UV inactive 1-carboxylate (br. s, 1H) 17 ethyl4-(4-((1- 2 b (400 MHz, DMSO-d₆) δ: 1.11-1.20 (m, 3H), 1.20 (s, 3H), Bm/z 394 (M + H)⁺ methylcyclohexyl)carbam- 1.21-1.24 (m, 9H), 1.33-1.84(m, 14H), 1.97-2.06 (m, (ES⁺), at 3.94 oyl)piperidin-1-yl)azepane-1-2H), 3.05-3.28 (m, 3H), 3.40-3.67 (m, 2H), 4.00-4.08 min, UV inactivecarboxylate (m, 2H), 7.10 (br. s, 1H) 18 ethyl 4-(4-(([1- 2 b (400 MHz,DMSO-d₆) δ: 0.89 (s, 3H), 1.14-1.30 (m, 6H), B m/z 394 (M + H)⁺methylcyclopentyl]methyl)car- 1.38-1.87 (m, 21H), 2.96 (d, J = 6.3, 2H),3.17-3.28 (m, (ES⁺), at 3.87 bamoyl)piperidin-1- 2H), 3.40-3.52 (m, 2H),4.04 (q, J = 6.8, 2H), 7.70 (br. s, min, UV inactiveyl)azepane-1-carboxylate 1H) 19 ethyl 4-(4-((2,2,2- 2 b (400 MHz,DMSO-d₆) δ: 1.17 (td, J = 7.1, 2.3, 3H), 1.30- C m/z 380 (M + H)⁺trifluoroethyl)carbamoyl)pi- 1.82 (m, 10H), 2.07-2.19 (m, 2H), 2.32-2.43(m, 2H), 2.66- (ES⁺), at 2.72 peridin-1-yl)azepane-1- 2.77 (m, 2H),3.19-3.27 (m, 2H), 3.43-3.46 (m, 2H), min, UV inactive carboxylate3.82-3.91 (m, 2H), 4.03 (qd, J = 6.9, 2.6, 2H), 8.42 (t, J = 6.2, 1H) 20ethyl 4-(4-((3,3,3-trifluoro- 2 b (400 MHz, DMSO-d₆) δ: 1.17 (td, J =7.0, 2.0, 3H), 1.30- C m/z 424 (M + H)⁺ 2-methoxypropyl)carbamoyl) 1.85(m, 10H), 2.03-2.19 (m, 2H), 2.35-2.45 (m, 2H), 2.66- (ES⁺), at 1.89piperidin-1-yl)azepane-1- 2.77 (m, 2H), 3.10-3.27 (m, 3H), 3.37-3.45 (m,2H), min, UV inactive carboxylate 3.47 (s, 3H), 3.84-3.92 (m, 2H), 4.03(qd, J = 7.0, 2.5, 2H), 8.05 (t, J = 5.7, 1H) 21 ethyl 4-(4- 2 b (400MHz, CDCl₃) δ: 1.26 (t, J = 7.0, 3H), 1.41-2.09 (m, B m/z 382 (M + H)⁺((tetrahydrofuran-3- 15H), 2.16-2.32 (m, 2H), 2.42-2.55 (m, 2H),2.76-2.95 (ES⁺), at 2.49 ylmethyl)carbamoyl)piperidin- (m, 2H),3.20-3.62 (m, 6H), 3.67-3.96 (m, 2H), 4.09- min, UV inactive1-yl)azepane-1- 4.18 (m, 2H), 5.73 (br. s, 1H) carboxylate 22 ethyl4-(4- 2 b (400 MHz, DMSO-d₆) δ: 1.13-1.23 (m, 3H), 1.40-2.30 (m, B m/z342 (M + H)⁺ ((methoxy(methyl))carbam- 13H), 2.38-2.45 (m, 1H),2.65-2.82 (m, 2H), 3.10 (s, 3H), (ES⁺), at 2.84oyl)piperidin-1-yl)azepane- 3.20-3.29 (m, 2H), 3.40-3.52 (m, 2H), 3.69(s, 3H), 4.04 min, UV inactive 1-carboxylate (q, J = 6.7, 2H) 23 ethyl4-(4-((propan-2- 2 b (400 MHz, DMSO-d₆) δ: 1.11 (d, J = 6.3, 6H), 1.18(td, J = B m/z 356 (M + H)⁺ yloxy))carbamoyl)piperidin- 7.0, 3.1, 3H),1.22-2.30 (m, 13H), 2.55-3.00 (m, 3H), (ES⁺), at 2.581-yl)azepane-1-carboxylate 3.15-3.29 (m, 2H), 3.40-3.55 (m, 2H),3.89-3.98 (m, min, UV inactive 1H), 4.04 (m, 2H), 10.80 (br. s, 1H) 24ethyl 4-(4-((2- 2 c (400 MHz, CD₃OD) δ: 1.28 (td, J = 7.1 , 3.2, 3H),1.42-1.88 C m/z 352 (M + H)⁺ methylallyl)carbamoyl)pi- (m, 11H),1.88-2.09 (m, 3H), 2.20-2.31 (m, 1H), 2.32- (ES⁺), at 0.81peridin-1-yl)azepane-1- 2.48 (m, 2H), 2.57 (t, J = 9.8, 1H), 2.85-2.98(m, 2H), 3.27- min, UV inactive carboxylate 3.41 (m, 2H), 3.51-3.64 (m,2H), 3.74 (s, 2H), 4.14 (qd, J = 7.1, 3.2, 2H), 4.83 (d, J = 1.3, 2H) 25ethyl 4-(4- 2 c (400 MHz, CD₃OD) δ: 0.95 (t, J = 7.3, 3H), 1.28 (td, J =7.1, C m/z 354 (M + H)⁺ (butylcarbamoyl)piperidin- 3.2, 3H), 1.32-1.42(m, 2H), 1.42-1.84 (m, 8H), 1.86- (ES⁺), at 0.861-yl)azepane-1-carboxylate 2.07 (m, 3H), 2.18 (tt, J = 10.2, 4.9, 1H),2.30-2.44 (m, min, UV inactive 2H), 2.55 (t, J = 9.2, 1H), 2.84-2.94 (m,2H), 3.18 (t, J = 7.1, 2H), 3.25-3.42 (m, 4H), 3.52-3.65 (m, 2H), 4.14(qd, J = 7.1, 3.3, 2H), 26 ethyl 4-(4- 2 c (400 MHz, CD₃OD) δ: 0.21-0.26(m, 1H), 0.26-0.32 (m, C m/z 380 (M + H)⁺((cyclopropylmethyl)(ethyl)car- 1H), 0.47 (ddd, J = 8.0, 5.9, 4.3, 1H),0.59 (ddd, J = 8.0, 5.9, (ES⁺), at 1.00 bamoyl)piperidin-1- 4.6, 1H),0.87-1.04 (m, 1H), 1.10 (t, J = 7.1, 2H), 1.17- min, UV inactiveyl)azepane-1-carboxylate 1.32 (m, 5H), 1.35-2.08 (m, 10H), 2.30-2.66 (m,4H), 2.78-2.93 (m, 2H), 3.20-3.38 (m, 3H), 3.41-3.62 (m, 4H), 4.11 (qd,J = 7.1, 3.5, 2H) 27 ethyl 4-(4-((1- 2 c (400 MHz, CD₃OD) δ: 1.24 (td, J= 7.1, 3.4, 3H), 1.39 (s, C m/z 366 (M + H)⁺ methylcyclobutyl)carbam-3H), 1.41-2.03 (m, 12H), 2.03-2.15 (m, 1H), 2.17-2.28 (ES⁺), at 0.96oyl)piperidin-1-yl)azepane-1- (m, 2H), 2.28-2.42 (m, 1H), 2.44-2.60 (m,1H), 2.77- min, UV inactive carboxylate 2.94 (m, 2H), 3.20-3.36 (m, 5H),3.48-3.58 (m, 3H), 4.10 (qd, J = 7.1, 3.4, 2H) 28 ethyl 4-(4-((1- 2 c(400 MHz, CD₃OD) δ: −0.05-0.13 (m, 2H), 0.33-0.47 (m, C m/z 380 (M + H)⁺cyclopropylpropan-2- 2H), 1.12 (d, J = 6.7, 3H), 1.24 (td, J = 7.1, 3.4,3H), 1.27- (ES⁺), at 0.98 yl)carbamoyl)piperidin-1- 1.37 (m, 2H),1.37-1.79 (m, 8H), 1.81-2.05 (m, 3H), 2.06- min, UV inactiveyl)azepane-1-carboxylate 2.20 (m, 1H), 2.25-2.42 (m, 2H), 2.45-2.57 (m,1H), 2.78-2.92 (m, 2H), 3.22-3.37 (m, 3H), 3.47-3.59 (m, 2H), 3.85-4.00(m, 1H), 4.10 (qd, J = 7.1, 3.4, 2H), 29 ethyl 4-(4-(cyclopent-3-en- 2 c(400 MHz, CD₃OD) δ: 1.24 (td, J = 7.1, 3.3, 3H), 1.34-1.79 C m/z 364(M + H)⁺ 1-ylcarbamoyl)piperidin-1- (m, 7H), 1.80-2.05 (m, 3H),2.06-2.23 (m, 3H), 2.24- (ES⁺), at 0.84 yl)azepane-1-carboxylate 2.41(m, 2H), 2.45-2.56 (m, 1H), 2.67 (ddd, J = 16.7, 8.0, min, UV inactive2.1, 2H), 2.77-2.91 (m, 2H), 3.22-3.36 (m, 3H), 3.48- 3.60 (m, 2H), 4.10(qd, J = 7.1, 3.4, 2H), 4.31-4.43 (m, 1H), 5.62-5.74 (m, 2H) 30 ethyl4-(4- 2 c (400 MHz, CD₃OD) δ: 1.24 (td, J = 7.1, 3.4, 3H), 1.32-1.80 Cm/z 366 (M + H)⁺ (cyclopentylcarbamoyl)pi- (m, 13H), 1.82-2.05 (m, 5H),2.06-2.21 (m, 1H), 2.26- (ES⁺), at 0.96 peridin-1-yl)azepane-1- 2.44 (m,2H), 2.48-2.62 (m, 1H), 2.79-2.98 (m, 2H), 3.20- min, UV inactivecarboxylate 3.41 (m, 3H), 3.48-3.60 (m, 2H), 3.96-4.18 (m, 3H), 31 ethyl4-(4-((2,3- 2 c (400 MHz, CD₃OD) δ: 0.85 (d, J = 6.9, 6H), 1.21 (s, 6H),C m/z 382 (M + H)⁺ dimethylbutan-2- 1.24 (td, J = 7.1 , 3.5, 3H),1.32-1.78 (m, 7H), 1.83-2.05 (ES⁺), at 1.18 yl)carbamoyl)piperidin-1-(m, 3H), 2.09-2.22 (m, 1H), 2.30-2.42 (m, 2H), 2.46- min, UV inactiveyl)azepane-1-carboxylate 2.60 (m, 1H), 2.80-2.95 (m, 2H), 3.22-3.40 (m,4H), 3.48- 3.59 (m, 2H), 4.10 (qd, J = 7.1, 3.3, 2H) 32 4-(4- 2 c (400MHz, CD₃OD) δ: 1.24 (td, J = 7.1, 3.4, 3H), 1.36-2.07 C m/z 338 (M + H)⁺(allylcarbamoyl)piperidin-1- (m, 10H), 2.16-2.29 (m, 1H), 2.33-2.52 (m,2H), 2.53- (ES⁺), at 0.74 yl)azepane-1-carboxylate 2.66 (m, 1H),2.84-3.03 (m, 2H), 3.20-3.37 (m, 3H), 3.48- min, UV inactive 3.61 (m,2H), 3.76 (dt, J = 5.4, 1.6, 2H), 4.10 (qd, J = 7.1, 3.3, 2H), 5.08(ddt, J = 23.4, 1.6, 1.6, 1H), 5.12 (ddt, J = 17.2, 1.6, 1.6, 1H),5.88-5.73 (m, 1H) 33 ethyl 4-(4-(2- 2 c (400 MHz, CD₃OD) δ: 1.13 (d, J =7.0, 1.5H), 1.19-1.32 (m, C m/z 380 (M + H)⁺ methylpiperidine-1- 4.5H),1.33-2.05 (m, 14H), 2.29-2.92 (m, 7H), 3.14- (ES⁺), at 1.10carbonyl)piperidin-1- 3.37 (m, 3H), 3.48-3.60 (m, 2H), 3.72-3.85 (m,1H), 4.10 min, UV inactive yl)azepane-1-carboxylate (qd, J = 7.1, 3.4,2H), 4.23-4.42 (m, 1H), 4.73-4.81 (m, 1H) 34 ethyl 4-(4- 2 c (400 MHz,DMSO-d₆at 100° C.) δ: 1.13-1.31 (m, 17H), 1.39- C m/z 382 (M + H)⁺(diisopropylcarbamoyl)pi- 1.71 (m, 5H), 1.74-1.89 (m, 3H), 2.18-2.30 (m,2H), (ES⁺), at 1.28 peridin-1-yl)azepane-1- 2.35-2.62 (m, 2H), 2.73-2.84(m, 2H), 3.182-3.32 (m, min, UV inactive carboxylate 2H), 3.41-3.54 (m,2H), 3.729-3.89 (m, 2H), 4.06 (q, J = 7.0, 2H) 35 ethyl4-(4-((2-methylbut-3- 2 c (400 MHz, CD₃OD) δ: 1.28 (td, J = 7.1, 3.3,3H), 1.32-1.55 C m/z 364 (M + H)⁺ yn-2- (m, 2H), 1.57 (s, 6H), 1.60-1.83(m, 5H), 1.87-2.09 (m, (ES⁺), at 1.19 yl)carbamoyl)piperidin-1- 3H),2.13-2.25 (m, 1H), 2.33-2.50 (m, 2H), 2.52-2.65 min, UV inactiveyl)azepane-1-carboxylate (s, 2H), 2.87-2.99 (m, 2H), 3.26-3.44 (m, 3H),3.52- 3.62 (m, 2H), 4.14 (qd, J = 7.1, 3.1, 2H) 36 ethyl4-(4-(methyl(prop-2- 2 c (400 MHz, CD₃OD) δ: 1.26 (td, J = 7.1, 3.3,3H), 1.41-1.83 C m/z 350 (M + H)⁺ yn-1- (m, 6H), 1.86-2.07 (m, 3H),2.36-2.82 (m, 5H), 2.83- (ES⁺), at 1.05 yl)carbamoyl)piperidin-1- 2.94(m, 2H), 2.96 (s, 1H), 3.15-3.18 (m, 2H), 3.24-3.28 min, UV inactiveyl)azepane-1-carboxylate (m, 1H), 3.33-3.42 (m, 2H), 3.50-3.62 (m, 2H),4.12 (qd, J = 7.1, 3.1, 2H), 4.18 (d, J = 2.4, 1H), 4.24 (d, J = 2.4,1H) 37 ethyl 4-(4-(((1- 2 c (400 MHz, CD₃OD) δ: 0.86 (t, J = 7.4, 3H),1.28 (td, J = 7.1, C m/z 394 (M + H)⁺ ethylcyclobutyl)methyl)car- 3.3,3H), 1.42-1.53 (m, 2H), 1.53-2.08 (m, 16H), 2.20- (ES⁺), at 1.25bamoyl)piperidin-1- 2.31 (m, 1H), 2.32-2.47 (m, 2H), 2.49-2.62 (m, 1H),2.84- min, UV inactive yl)azepane-1-carboxylate 2.96 (m, 2H), 3.24 (s,2H), 3.26-3.44 (m, 3H), 3.52- 3.63 (m, 2H), 4.14 (qd, J = 7.1, 3.3, 2H)38 ethyl 4-(4-((1,1,1-trifluoro- 2 c (400 MHz, DMSO-d₆) δ: 1.09-1.18 (m,3H), 1.19-1.24 (m, B m/z 408 (M + H)⁺ 2-methylpropan-2- 2H), 1.43 (s,6H), 1.60-2.30 (m, 10H), 2.39-2.46 (m, 2H), (ES⁺), at 3.52yl))carbamoyl)piperidin-1- 2.75-3.00 (m, 2H), 3.13-3.29 (m, 2H),3.34-3.61 (m, min, UV inactive yl)azepane-1-carboxylate 2H), 3.97-4.02(m, 2H), 7.90 (br. s, 1H) 39 ethyl 4-(4-((2- 2 b (400 MHz, CD₃OD) δ:0.09-0.02 (m, 1H), 0.26-0.11 (m, C m/z 380 (M + H)⁺cyclopropylpropyl)carbam- 2H), 0.61-0.33 (m, 3H), 0.99-0.80 (m, 3H),1.16-0.99 (ES⁺), at 1.06 oyl)piperidin-1-yl)azepane-1- (m, 2H),1.34-1.20 (m, 3H), 1.79-1.55 (m, 2H), 2.16- min, UV inactive carboxylate1.81 (m, 6H), 2.28-2.18 (m, 1H), 2.55-2.42 (m, 1H), 3.00 (s, 2H),3.21-3.04 (m, 3H), 3.50-3.24 (m, 4H), 3.64- 3.54 (m, 1H), 3.70 (dt, J =14.5, 4.9 Hz, 1H), 4.22-4.04 (m, 2H) 40 ethyl 4-(4-fluoro-4-((2- 3 b(400 MHz, DMSO-d₆) δ: 0.81 (d, J = 6.8, 6H), 1.14-1.20 (m, B m/z 372(M + H)⁺ methylpropyl)carbamoyl)pi- 3H), 1.32-2.10 (m, 10H), 2.30-2.45(m, 2H), 2.55-2.67 (ES⁺), at 3.62 peridin-1-yl)azepane-1- (m, 2H),2.87-2.99 (m, 4H), 3.15-3.29 (m, 2H), 3.40- min, UV inactive carboxylate3.55 (m, 2H), 4.01-4.05 (m, 2H), 8.08 (br. s, 1H) 41 ethyl4-(4-fluoro-4-((1,1- 3 b (400 MHz, DMSO-d₆) δ: 0.71 (t, J = 7.4, 3H),1.11-1.18 (m, B m/z 386 (M + H)⁺ dimethylpropyl)carbamoyl) 3H), 1.19 (s,6H), 1.35-2.49 (m, 15H), 3.07-3.25 (m, 4H), (ES⁺), at 4.31piperidin-1-yl)azepane-1- 3.35-3.60 (m, 2H), 4.00 (q, J = 6.8, 2H), 7.17(br. s, 1H) min, UV inactive carboxylate 42 ethyl 4-(4-fluoro-4- 3 b(400 MHz, DMSO-d₆) δ: 1.12-1.30 (m, 5H), 1.33-2.45 (m, B m/z 384 (M +H)⁺ ((cyclobutylmethyl)carbam- 18H), 3.06-3.14 (m, 2H), 3.20-3.29 (m,2H), 3.35-3.50 (ES⁺), at 3.96 oyl)piperidin-1-yl)azepane-1- (m, 2H),3.53-3.62 (m, 2H), 4.00 (q, J = 6.7, 2H), 8.16 (br. s, 1H) min, UVinactive carboxylate 43 ethyl 4-(4-fluoro-4-((tert- 3 d (400 MHz,DMSO-d₆) δ: 1.10-1.17 (m, 3H), 1.24 (s, 9H), B m/z 372 (M + H)⁺butyl)carbamoyl)piperidin- 1.30-2.05 (m, 11H), 2.24-2.43 (m, 2H),2.53-2.69 (m, (ES⁺), at 3.90 1-yl)azepane-1-carboxylate 2H), 3.10-3.29(m, 2H), 3.32-3.45 (m, 2H), 3.96-4.02 min, UV inactive (m, 2H), 7.06(br. s, 1H) 44 ethyl 4-(4-fluoro-4-((2,3- 3 d (400 MHz, DMSO-d₆) δ: 0.76(d, J = 6.9, 6H), 1.11-1.19 (m, B m/z 400 (M + H)⁺ dimethylbutan-2- 9H),1.26-2.01 (m, 11H), 2.25-2.43 (m, 3H), 2.52-2.64 (ES⁺), at 4.47yl)carbamoyl)piperidin-1- (m, 2H), 3.10-3.24 (m, 2H), 3.34-3.45 (m, 2H),3.95- min, UV inactive yl)azepane-1-carboxylate 4.02 (m, 2H), 6.82 (br.s, 1H) 45 ethyl 4-(4-fluoro-4-((1- 3 d (400 MHz, DMSO-d₆) δ: −0.09-−0.03(m, 1H), 0.03-0.08 B m/z 398 (M + H)⁺ cyclopropylpropan-2- (m, 1H),0.26-0.32 (m, 1H), 0.33-0.48 (m, 1H), 0.79- (ES⁺), at 4.04yl)carbamoyl)piperidin-1- 0.94 (m, 4H), 1.13 (t, J = 6.9, 3H), 1.26-2.05(m, 11H), min, UV inactive yl)azepane-1-carboxylate 2.25-2.43 (m, 3H),2.52-2.65 (m, 2H), 2.90-3.00 (m, 1H), 3.05-3.21 (m, 3H), 3.34-3.45 (m,2H), 3.99 (qd, J = 6.9, 2.0, 2H), 7.95 (br. s, 1H) 46 ethyl4-(4-fluoro-4-((2,2- 3 d (400 MHz, DMSO-d₆) δ: 0.78 (s, 9H), 1.13 (t, J= 6.9, 3H), B m/z 386 (M + H)⁺ dimethylpropyl)carbamoyl) 1.30-2.05 (m,10H), 2.26-2.44 (m, 3H), 2.53-2.69 (m, (ES⁺), at 4.01piperidin-1-yl)azepane-1- 2H), 2.88 (d, J = 6.5, 2H), 3.11-3.24 (m, 2H),3.33-3.46 min, UV inactive carboxylate (m, 2H), 3.99 (q, J = 6.9, 2H),7.83 (br. s, 1H) 47 ethyl 4-(4-fluoro-4-((1- 3 d (400 MHz, DMSO-d₆) δ:0.45-0.49 (m, 2H), 0.56-0.61 (m, B m/z 370 (M + H)⁺methylcyclopropyl)carbam- 2H), 1.13 (t, J = 6.9, 3H), 1.21 (s, 3H),1.26-2.00 (m, 10H), (ES⁺), at 3.25 oyl)piperidin-1-yl)azepane-1-2.24-2.44 (m, 3H), 2.52-2.65 (m, 2H), 3.10-3.22 (m, min, UV inactivecarboxylate 2H), 3.33-3.46 (m, 2H), 3.99 (q, J = 6.9, 2H), 8.16 (br. s,1H) 48 ethyl 4-(4-fluoro-4-((1- 3 d (400 MHz, DMSO-d₆) δ: 1.13 (t, J =6.9, 3H), 1.26 (s, 3H), B m/z 398 (M + H)⁺ methylcyclopentyl)carbam-1.30-2.05 (m, 18H), 2.25-2.44 (m, 3H), 2.53-2.65 (m, (ES⁺), at 4.24oyl)piperidin-1-yl)azepane-1- 2H), 3.10-3.23 (m, 2H), 3.33-3.45 (m, 2H),3.95-4.02 min, UV inactive carboxylate (m, 2H), 7.23 (br. s, 1H) 49ethyl 4-(4-fluoro-4--(((1- 3 d (400 MHz, DMSO-d₆) δ: 0.75 (t, J = 7.3,3H), 1.13 (t, J = 6.9, B m/z 412 (M + H)⁺ ethylcyclobutyl)methyl)car-3H), 1.25-2.05 (m, 18H), 2.26-2.44 (m, 3H), 2.53-2.65 (ES⁺), at 4.53bamoyl)piperidin-1- (m, 2H), 3.08 (d, J = 6.0, 2H), 3.10-3.25 (m, 2H),3.34- min, UV inactive yl)azepane-1-carboxylate 3.46 (m, 2H), 3.96-4.02(m, 2H), 7.85 (d, J = 2.7, 1H) 50 ethyl 4-(4-fluoro-4-((1- 3 d (400 MHz,DMSO-d₆) δ: 1.13 (t, J = 6.9, 3H), 1.32 (s, 3H), B m/z 384 (M + H)⁺methylcyclobutyl)carbam- 1.34-2.00 (m, 14H), 2.12-2.24 (m, 2H),2.25-2.44 (m, (ES⁺), at 3.37 oyl)piperidin-1-yl)azepane-1- 3H),2.53-2.62 (m, 2H), 3.10-3.23 (m, 2H), 3.32-3.45 min, UV inactivecarboxylate (m, 2H), 3.99 (q, J = 6.7, 2H), 7.84 (br. s, 1H) 51 ethyl4-(4-fluoro-4- 3 d (400 MHz, DMSO-d₆) δ: 1.10-1.16 (m, 3H), 1.27-2.05(m, B m/z 384 (M + H)⁺ ((cyclopentyl)carbamoyl)pi- 19H), 2.20-2.44 (m,3H), 2.53-2.65 (m, 2H), 3.10-3.25 (ES⁺), at 3.81 peridin-1-yl)azepane-1-(m, 2H), 3.33-3.45 (m, 2H), 3.93-4.02 (m, 2H), 7.86 (d, J = min, UVinactive carboxylate 2.3, 1H) 52 ethyl 4-(4-fluoro-4- 3 d (400 MHz,DMSO-d₆) δ: 0.09-0.12 (m, 2H), 0.30-0.36 (m, B m/z 370 (M + H)⁺((cyclopropylmethyl)carbam- 2H), 0.85-0.94 (m, 1H), 1.13 (t, J = 7.1,3H), 1.25-2.02 (ES⁺), at 3.48 oyl)piperidin-1- (m, 10H), 2.25-2.44 (m,3H), 2.53-2.65 (m, 2H), 2.92 (t, J = min, UV inactiveyl)azepane-1-carboxylate 6.2, 2H), 3.10-3.23 (m, 2H), 3.33-3.46 (m, 2H),3.99 (q, J = 6.9, 2H), 8.10 (br. s, 1H) 53 ethyl 4-(4-fluoro-4- 3 d (400MHz, DMSO-d₆) δ: 1.13 (t, J = 6.9, 3H), 1.26-2.05 (m, B m/z 398 (M + H)⁺((cyclopentylmethyl)carbam- 19H), 2.25-2.44 (m, 3H), 2.53-2.65 (m, 2H),2.96 (t, J = (ES⁺), at 4.19 oyl)piperidin-1-yl)azepane- 6.4, 2H),3.10-3.23 (m, 2H), 3.35-3.48 (m, 2H), 3.95- min, UV inactive1-carboxylate 4.02 (m, 2H), 8.05 (br. s, 1H) 54 ethyl 4-(4-fluoro-4-((2-3 d (400 MHz, DMSO-d₆) δ: 0.22-0.30 (m, 4H), 1.08-1.17 (m, B m/z 398(M + H)⁺ cyclopropylpropan-2- 9H), 1.25-2.05 (m, 11H), 2.25-2.43 (m,3H), 2.53-2.65 (ES⁺), at 4.36 yl)carbamoyl)piperidin-1- (m, 2H),3.10-3.23 (m, 2H), 3.42-3.50 (m, 2H), 3.99 (q, J = min, UV inactiveyl)azepane-1-carboxylate 6.8, 2H), 6.83 (d, J = 2.3, 1H) 55 ethyl4-(4-fluoro-4- 3 d (400 MHz, DMSO-d₆) δ: 1.13 (td, J = 7.1, 1.7, 3H),1.25- B m/z 370 (M + H)⁺ ((cyclobutyl)carbamoyl)pi- 2.10 (m, 13H),2.30-2.44 (m, 3H), 2.53-2.65 (m, 2H), (ES⁺), at 3.36peridin-1-yl)azepane-1- 3.10-3.24 (m, 2H), 3.32-3.45 (m, 4H), 3.52-3.60(m, min, UV inactive carboxylate 2H), 3.99 (qd, J = 6.9, 1.9, 2H), 8.23(br. s, 1H) 56 ethyl 4-(4-methyl-4-((2- 4 b (400 MHz, DMSO-d₆) δ:0.80-0.90 (m, 6H), 1.14-1.28 (m, B m/z 368 (M + H)⁺methylpropyl)carbamoyl)pi- 8H), 1.46-1.61 (m, 3H), 1.65-2.10 (m, 7H),2.25-2.35 (ES⁺), at 3.23 peridin-1-yl)azepane-1- (m, 2H), 2.86-2.94 (m,3H), 3.06-3.11 (m, 1H), 3.15- min, UV inactive carboxylate 3.29 (m, 2H),3.40-3.58 (m, 2H), 4.00-4.08 (m, 2H), 7.89 (t, J = 5.6, 1H) 57prop-2-yn-1-yl-4-(4-((2- 5 e (400 MHz, DMSO-d₆) δ: 0.81 (d, J = 6.8,6H), 1.35-1.92 B m/z 364 (M + H)⁺ methylpropyl)carbamoyl)pi- (m, 14H),2.32-2.45 (m, 1H), 2.65-2.78 (m, 2H), 2.85 (t, J = (ES⁺), at 3.20peridin-1-yl)azepane-1- 6.2, 2H), 3.17-3.29 (m, 2H), 3.40-3.52 (m, 3H),4.67 (t, min, UV inactive carboxylate J = 2.5, 2H), 7.70 (br. s, 1H) 58but-2-yn-1-yl-4-(4-((2- 5 e (400 MHz, DMSO-d₆) δ: 0.81 (d, J = 6.8, 6H),1.33-1.89 (m, B m/z 378 (M + H)⁺ methylpropyl)carbamoyl)pi- 13H),1.97-2.20 (m, 4H), 2.32-2.45 (m, 1H), 2.65-2.78 (ES⁺), at 3.39peridin-1-yl)azepane-1- (m, 2H), 2.84 (t, J = 6.3, 2H), 3.14-3.29 (m,2H), 3.38- min, UV inactive carboxylate 3.50 (m, 2H), 4.61-4.64 (m, 2H),7.68 (br. s, 1H) 59 2-fluoroethyl-4-(4-((2- 5 e (400 MHz, CDCl₃) δ: 0.91(d, J = 6.8, 6H), 1.40-2.70 (m, B m/z 372 (M + H)⁺methylpropyl)carbamoyl)pi- 15H), 2.80-2.98 (m, 2H), 3.08 (t, J = 6.4,2H), 3.22-3.40 (ES⁺), at 2.95 peridin-1-yl)azepane-1- (m, 2H), 3.46-3.70(m, 2H), 4.25-4.32 (m, 1H), 4.34- min, UV inactive carboxylate 4.39 (m,1H), 4.50-4.55 (m, 1H), 4.62-4.67 (m, 1H), 5.58 (br. s, 1H) 602-methoxyethyl-4-(4-((2- 5 e (400 MHz, CDCl₃) δ: 0.90 (d, J = 6.8, 6H),1.25-2.68 (m, B m/z 384 (M + H)⁺ methylpropyl)carbamoyl)pi- 16H),2.85-2.98 (m, 1H), 3.07 (t, J = 6.4, 2H), 3.22-3.35 (ES⁺), at 2.81peridin-1-yl)azepane-1- (m, 2H), 3.38 (s, 3H), 3.47-3.68 (m, 4H),4.20-4.27 (m, min, UV inactive carboxylate 2H), 5.60 (br. s, 1H) 612-propyl-4-(4-((2- 5 e (400 MHz, DMSO-d₆) δ: 0.81 (d, J = 6.5, 6H), 0.89(td, J = B m/z 368 (M + H)⁺ methylpropyl)carbamoyl)pi- 7.3, 2.9, 3H),1.30-1.91 (m, 12H), 2.00-2.25 (m, 2H), (ES⁺), at 3.49peridin-1-yl)azepane-1- 2.35-2.45 (m, 2H), 2.70-2.80 (m, 2H), 2.84 (t, J= 6.2, min, UV inactive carboxylate 2H), 3.15-3.55 (m, 5H), 3.94 (td, J= 6.5, 2.7, 2H), 7.70 (br. s, 1H) 62 2,2,2-trifluoroethyl-4-(4-((2- 5 e(400 MHz, DMSO-d₆) δ: 0.82 (d, J = 6.8, 6H), 1.30-2.45 (m, B m/z 408(M + H)⁺ methylpropyl)carbamoyl)pi- 16H), 2.68-2.79 (m, 1H), 2.85 (t, J= 5.8, 2H), 3.20-3.29 (ES⁺), at 3.55 peridin-1-yl)azepane-1- (m, 2H),3.43-3.54 (m, 2H), 4.71 (qd, J = 9.0, 3.0, 2H), min, UV inactivecarboxylate 7.70 (br. s, 1H) 63 ethyl (4S)-4-[4-((2- 6-(S) f (400 MHz,DMSO-d₆) δ: 0.78 (d, J = 6.5, 6H), 1.14 (td, J = B m/z 354 (M + H)⁺methylpropyl)methylcarbam- 7.0, 2.7, 3H), 1.25-2.00 (m, 14H), 2.05-2.25(m, 3H), 2.81 (ES⁺), at 3.10 oyl)piperidin-1- (t, J = 6.2, 2H),3.10-3.29 (m, 2H), 3.40-3.50 (m, 2H), min, UV inactiveyl]azepane-1-carboxylate 4.00 (q, J = 6.9, 2H), 7.71 (br. s, 1H) 64ethyl (4R)-4-[4-((2- 6-(R) f (400 MHz, DMSO-d₆) δ: 0.78 (d, J = 6.5,6H), 1.12-1.18 (m, B m/z 354 (M + H)⁺ methylpropyl)methylcarbam- 3H),1.32-2.00 (m, 14H), 2.05-2.30 (m, 3H), 2.83 (t, J = (ES⁺), at 3.30oyl)piperidin-1- 6.2, 2H), 3.02-3.29 (m, 2H), 3.40-3.50 (m, 2H), 4.00(q, J = min, UV inactive yl]azepane-1-carboxylate 6.9, 2H), 7.87 (br. s,1H) 65 ethyl (4S)-4-{4-[(1- 6-(S) f (400 MHz, DMSO-d₆) δ: 1.13 (td, J =7.1, 2.3, 3H), 1.28 (s, B m/z 366 (M + H)⁺ methylcyclobutyl)carbam- 3H),1.29-1.60 (m, 7H), 1.60-1.87 (m, 7H), 1.90-1.99 (m, (ES⁺), at 3.28oyl]piperidin-1-yl}azepane-1- 1H), 2.02-2.24 (m, 4H), 2.32-2.40 (m, 1H),2.65-2.73 min, UV inactive carboxylate (m, 2H), 3.06-3.22 (m, 2H),3.35-3.48 (m, 2H), 3.98 (qd, J = 7.0, 2.7, 2H), 7.68 (br. s, 1H) 66ethyl (4R)-4-{4-[(1- 6-(R) f (400 MHz, DMSO-d₆) δ: 1.13 (td, J = 6.9,1.8, 3H), 1.28 (s, B m/z 366 (M + H)⁺ methylcyclobutyl)carbam- 3H),1.30-1.59 (m, 7H), 1.61-1.85 (m, 7H), 1.85-1.98 (m, (ES⁺), at 3.2oyl]piperidin-1-yl}azepane-1- 1H), 1.98-2.21 (m, 4H), 2.30-2.40 (m, 1H),2.60-2.69 min, UV inactive carboxylate (m, 2H), 3.07-3.23 (m, 2H),3.33-3.48 (m, 2H), 3.98 (qd, J = 7.0, 2.7, 2H), 7.65 (br. s, 1H) 67ethyl (4S)-4-[4-(tert- 6-(S) f (400 MHz, DMSO-d₆) δ: 1.11-1.19 (m, 3H),1.21 (s, 9H), B m/z 354 (M + H)⁺ butylcarbamoyl)piperidin-1- 1.27-1.51(m, 4H), 1.54 (m, 3H), 1.65-1.80 (m, 3H), 1.95- (ES⁺), at 3.17yl]azepane-1-carboxylate 2.12 (m, 3H), 2.33-2.40 (m, 1H), 2.65-2.74 (m,2H), min, UV inactive 3.12-3.26 (m, 2H), 3.37-3.50 (m, 2H), 4.02 (qd, J= 6.9, 2.5, 2H), 7.23 (br. s, 1H) 68 ethyl (4R)-4-[4-(tert- 6-(R) f (400MHz, DMSO-d₆) δ: 1.11-1.20 (m, 3H), 1.22 (s, 9H), B m/z 354 (M + H)⁺butylcarbamoyl)piperidin-1- 1.27-1.52 (m, 4H), 1.52-1.63 (m, 3H),1.67-1.90 (m, 3H), (ES⁺), at 3.17 yl]azepane-1-carboxylate 1.93-2.15 (m,3H), 2.35-2.41 (m, 1H), 2.65-2.74 (m, min, UV inactive 2H), 3.11-3.28(m, 2H), 3.37-3.50 (m, 2H), 4.03 (qd, J = 7.0, 2.5, 2H), 7.23 (br. s,1H) 69 ethyl 4-(4-{[(1- 2 c (400 MHz, DMSO-d₆) δ: 1.01 (s, 3H), 1.17(td, J = 7.0, 2.4, B m/z 380 (M + H)⁺ methylcyclobutyl)methyl]car- 3H),1.30-1.45 (m, 2H), 1.48-1.66 (m, 7H), 1.68-1.85 (ES⁺), at 3.63bamoyl}piperidin-1- (m, 7H), 2.07-2.18 (m, 2H), 2.31-2.41 (m, 2H), 2.61-min, UV inactive yl)azepane-1-carboxylate 2.88 (m, 2H), 3.02 (d, J =6.3, 2H), 3.12-3.27 (m, 2H), 3.40- 3.45 (m, 2H), 4.02 (qd, J = 7.0, 2.9,2H), 7.71 (br. s, 1H) 70 ethyl 4-(4-{[1- 2 b (300 MHz, DMSO-d₆) δ: 1.12(t, J = 7.0, 3H), 1.22-1.52 (m, B m/z 420 (M + H)⁺(trifluoromethyl)cyclobutyl]car- 4H), 1.52-1.60 (m, 2H), 1.64-1.94 (m,5H), 1.94-2.18 (ES⁺), at 5.46 bamoyl}piperidin-1- (m, 3H), 2.25-2.43 (m,4H), 2.52-2.87 (m, 4H), 3.07-3.24 min, UV inactiveyl)azepane-1-carboxylate (m, 2H), 3.33-3.49 (m, 2H), 3.99 (q, J = 7.0,2H), 8.16 (br. s, 1H) 71 ethyl 4-{4-[(2- 2 b (300 MHz, DMSO-ds) δ: 0.71(d, J = 6.9, 1H), 0.81-0.88 (m, B m/z 380 (M + H)⁺methylcyclopentyl)carbam- 2H), 0.98-1.18 (m, 3H), 1.19-1.48 (m, 5H),1.48-1.85 (m, (ES⁺), at 5.49 oyl]piperidin-1-yl}azepane-1- 11H),1.86-1.99 (m, 1H), 2.01-2.23 (m, 3H), 2.30-2.38 min, UV inactivecarboxylate (m, 1H), 2.59-2.86 (m, 3H), 3.08-3.25 (m, 2H), 3.35-3.56 (m,2H), 3.92-4.04 (m, 2H), 7.39-7.55 (m, 1H) 72 ethyl 4-{4-[(3- 2 b (400MHz, DMSO-d₆) δ: 1.13-1.21 (m, 3H), 1.21-1.31 (m, B m/z 364 (M + H)⁺methylidenecyclobutyl)car- 4H), 1.41-1.65 (m, 2H), 2.07-1.65 (m, 7H),2.05-2.20 (m, (ES⁺), at 3.14 bamoyl]piperidin-1- 1H), 2.25-2.42 (m, 1H),2.57-2.72 (m, 1H), 2.82-2.95 (m, min, UV inactiveyl}azepane-1-carboxylate 2H), 2.97-3.05 (m, 1H), 3.09-3.19 (m, 1H),3.19-3.30 (m, 2H), 3.46-3.72 (m, 2H), 4.05 (q, J = 6.8, 2H), 4.11-4.21(m, 1H), 4.82 (s, 2H), 8.22-8.44 (m, 1H) 73 ethyl 4-{4-[(3- 2 b (400MHz, DMSO-d₆) δ: 1.01 (d, J = 7.0, 2H), 1.09 (d, J = B m/z 366 (M + H)⁺methylcyclobutyl)carbam- 7.0, 1H), 1.13-1.23 (m, 3H), 1.35-1.65 (m, 9H),1.72- (ES⁺), at 3.37 oyl]piperidin-1-yl}azepane-1- 1.87 (m, 4H),1.89-2.05 (m, 2H), 2.09-2.37 (m, 4H), 2.70- min, UV inactive carboxylate2.79 (m, 2H), 3.07-3.27 (m, 2H), 3.41-3.47 (m, 2H), 3.94-4.12 (m, 2.5H),4.26-4.31 (m, 0.5H), 7.88-7.96 (m, 1H) 74 ethyl 4-{4-[(1- 2 b (400 MHz,DMSO-d₆) δ: 0.71 (t, J = 7.3, 3H), 1.17 (td, J = B m/z 380 (M + H)⁺ethylcyclobutyl)carbamoyl] 7.0, 2.8, 3H), 1.32-1.49 (m, 3H), 1.50-1.83(m, 11H), 1.84- (ES⁺), at 3.54 piperidin-1-yl}azepane-1- 1.92 (m, 3H),1.96-2.25 (m, 5H), 2.69-2.79 (m, 2H), min, UV inactive carboxylate3.15-3.27 (m, 2H), 3.39-3.56 (m, 2H), 4.02 (qd, J = 7.0, 2.6, 2H), 7.65(br. s, 1H) 75 ethyl 4-(4-{[2- 2 b (400 MHz, DMSO-d₆) δ: 1.11-1.16 (m,3H) 1.23-1.55 (m, B m/z 363 (M + H)⁺ (²H₃)methyl(²H₆)propyl]car- 7H),1.65-1.80 (m, 3H), 1.92-2.22 (m, 3H), 2.23-2.41 (ES⁺), at 3.08bamoyl}piperidin-1- (m, 1H), 2.65-2.75 (m, 2H), 3.07-3.23 (m, 2H), 3.36-min, UV inactive yl)azepane-1-carboxylate 3.42 (m, 2H), 3.96-4.00 (m,2H), 7.63 (br. s, 1H) 76 ethyl 4-{4-[(1-fluoro-2- 2 b (400 MHz, DMSO-d₆)δ: 1.11-1.17 (m, 9H), 1.25-1.49 (m, B m/z 372 (M + H)⁺ methylpropan-2-4H), 1.50-1.63 (m, 4H), 1.69-1.84 (m, 3H), 1.95-2.24 (ES⁺), at 3.07yl)carbamoyl]piperidin-1- (m, 3H), 2.67-2.75 (m, 2H), 3.09-3.23 (m, 2H),3.34- min, UV inactive yl}azepane-1-carboxylate 3.55 (m, 2H), 3.98 (qd,J = 6.9, 2.5, 2H), 4.38 (d, J = 48, 2H), 7.41 (br. s, 1H) 77 ethyl4-{4-[(2- 2 b (400 MHz, DMSO-d₆) δ: 0.79 (t, J = 7.3, 3H), 1.09-1.20 (m,B m/z 382 (M + H)⁺ methylpentan-2- 11H), 1.28-1.63 (m, 9H), 1.65-1.85(m, 4H), 1.91-2.18 (ES⁺), at 3.97 yl)carbamoyl]piperidin-1- (m, 3H),2.64-2.74 (m, 2H), 3.13-3.22 (m, 2H), 3.34- min, UV inactiveyl}azepane-1-carboxylate 3.48 (m, 2H), 3.98 (qd, J = 6.9, 2.7, 2H), 7.10(br. s, 1H) 78 ethyl 4-{4-methyl-4-[(1- 4 b (400 MHz, DMSO-d₆) δ:0.97-1.25 (m, 8H), 1.29-1.38 (m, B m/z 380 (M + H)⁺methylcyclobutyl)carbam- 3H), 1.40-1.60 (m, 3H), 1.62-1.75 (m, 3H),1.77-1.96 (ES⁺), at 3.40 oyl]piperidin-1-yl}azepane-1- (m, 4H),1.99-2.07 (m, 1H), 2.09-2.33 (m, 4H), 2.69- min, UV inactive carboxylate2.89 (m, 2H), 3.07-3.20 (m, 4H), 3.40-3.56 (m, 2H), 3.82- 4.12 (m, 2H),7.21-7.56 (m, 1H) 79 ethyl 4-{4-methoxy-4-[(1- 7 e (400 MHz, DMSO-d₆) δ:1.17 (td, J = 7.1, 2.1, 3H), 1.35 (s, B m/z 396 (M + H)⁺methylcyclobutyl)carbam- 3H), 1.36-1.50 (m, 2H), 1.50-1.64 (m, 1H),1.64-1.94 (m, (ES⁺), at 3.48 oyl]piperidin-1-yl}azepane-1- 11H),2.09-2.27 (m, 2H), 2.24-2.40 (m, 4H), 3.07 (s, 3H), min, UV inactivecarboxylate 3.12-3.28 (m, 2H), 3.28-3.55 (m, 3H), 4.02 (qd, J = 7.0,2.3, 2H), 7.70 (br. s, 1H) 80 but-2-yn-1-yl 4-{4-methoxy- 7 e (400 MHz,DMSO-d₆) δ: 1.35 (s, 3H), 1.37-1.53 (m, 2H), B m/z 420 (M + H)⁺ 4-[(1-1.54-1.64 (m, 1H), 1.66-1.84 (m, 12H), 1.85-1.92 (m, (ES⁺), at 3.90methylcyclobutyl)carbam- 3H), 2.13-2.26 (m, 2H), 2.30-2.42 (m, 4H), 3.08(s, 3H), min, UV inactive oyl]piperidin-1-yl}azepane-1- 3.14-3.28 (m,2H), 3.40-3.63 (m, 2H), 4.63 (s, 2H), 7.66 carboxylate (br. s, 1H) 81ethyl 4-(4-methoxy-4-{[(1- 8 b (400 MHz, DMSO-d₆) δ: 1.04 (s, 3H),1.10-1.23 (m, 3H), B m/z 410 (M + H)⁺ methylcyclobutyl)methyl]car-1.32-1.46 (m, 2H), 1.48-1.64 (m, 4H), 1.64-1.94 (m, (ES⁺), at 4.22bamoyl}piperidin-1- 11H), 2.28-2.43 (m, 4H), 3.07 (d, J = 6.3, 2H), 3.10(s, 3H), min, UV inactive yl)azepane-1-carboxylate 3.14-3.27 (m, 2H),3.38-3.49 (m, 2H), 3.91-4.07 (m, 2H), 7.68-7.86 (m, 1H) 82 ethyl4-{4-cyano-4-[(1- 9 b (400 MHz, DMSO-d₆) δ: 1.09-1.15 (m, 2H), 1.20-1.25(m, 3H), B m/z 391 (M + H)⁺ methylcyclobutyl)carbam- 1.32 (s, 3H),1.36-1.47 (m, 2H), 1.48-1.61 (m, 1H), 1.67-1.90 (ES⁺), at 3.54oyl]piperidin-1-yl}azepane-1- (m, 7H), 1.93-1.99 (m, 1H), 2.08-2.22 (m,2H), 2.29-2.45 (m, min, UV inactive carboxylate 3H), 2.56-2.83 (m, 2H),3.07-3.24 (m, 2H), 3.36-3.43 (m, 2H), 3.53-3.61 (m, 1H), 3.94-4.02 (m,2H), 8.13 (br. s, 1H)

Biological Activity

Example A

Phospho-ERK1/2 Assays

Functional assays were performed using the Alphascreen Surefirephospho-ERK1/2 assay (Crouch & Osmond, Comb. Chem. High ThroughputScreen, 2008). ERK1/2 phosphorylation is a downstream consequence ofboth Gq/11 and Gi/o protein coupled receptor activation, making ithighly suitable for the assessment of M1 M3 (Gq/11 coupled) and M2, M4receptors (Gi/o coupled), rather than using different assay formats fordifferent receptor subtypes. CHO cells stably expressing the humanmuscarinic M1, M2, M3 or M4 receptor were plated (25K/well) onto 96-welltissue culture plates in MEM-alpha+10% dialysed FBS. Once adhered, cellswere serum-starved overnight, Agonist stimulation was performed by theaddition of 5 μL agonist to the cells for 5 min (37° C.). Media wasremoved and 50 μL of lysis buffer added. After 15 min, a 4 μL sample wastransferred to 384-well plate and 7 μL of detection mixture added.Plates were incubated for 2 h with gentle agitation in the dark and thenread on a PHERAstar plate reader.

pEC₅₀ and E_(max) figures were calculated from the resulting data foreach receptor subtype.

The results are set out in Table 3 below.

TABLE 3 Muscarinic Activity pEC₅₀ M1 pEC₅₀ M2 pEC₅₀ M3 pEC₅₀ M4 Ex. (%Emax (% Emax (% Emax (% Emax No. cf. ACh) cf. ACh) cf. ACh) cf. ACh) ACh8.31 (103) 7.81 (104) 8.16 (112) 8.08 (110) 3 6.70 (116) <4.7 (6) <4.7(4) 6.25 (85) 6 7.07 (113) <4.7 (10) <4.7 (33) 5.98 (76) 7 7.09 (111)<4.7 (2) <4.7 (14) 6.72 (80) 8 6.82 (93) <4.7 (3) <4.7 (2) 5.78 (55) 96.93 (125) <4.7 (6) 4.88 (23) 6.10 (41) 11 7.22 (117) <4.7 (7) <4.7 (11)6.37 (67) 15 6.95 (107) <4.7 (5) <4.7 (12) 6.26 (67) 17 7.21 (104) <4.7(0) <4.7 (5) 6.14 (46) 18 7.08 (101) <4.7 (7) <4.7 (4) 6.23 (39) 26 6.35(95) <4.7 (7) <4.7 (0) 6.51 (51) 27 7.34 (117) <4.7 (56) <4.7 (5) 6.37(88) 30 7.24 (132) <4.7 (3) <4.7 (33) 6.65 (104) 31 7.50 (122) <4.7 (0)<4.7 (13) 6.91 (90) 37 7.86 (87) <4.7 (8) <4.7 (10) 6.72 (75) 39 7.14(96) <4.7 (2) <4.7 (8) <4.7 (13) 40 7.34 (106) <4.7 (13) <4.7 (9) 6.07(89) 41 7.40 (97) <4.7 (41) <4.7 (12) 6.59 (88) 44 7.50 (104) <4.7 (19)<4.7 (5) 6.38 (113) 45 6.95 (101) <4.7 (29) <4.7 (1) 5.92 (59) 46 6.98(90) <4.7 (9) <4.7 (1) 5.97 (63) 48 7.21 (88) <4.7 (12) <4.7 (12) 6.27(73) 50 7.71 (102) <4.7 (17) <4.7 (2) 6.22 (90) 51 7.29 (107) <4.7 (12)<4.7 (6) 6.15 (93) 52 6.64 (95) <4.7 (9) <4.7 (5) 6.30 (84) 53 7.01(122) <4.7 (9) <4.7 (17) 6.01 (90) 54 7.31 (124) <4.7 (15) <4.7 (6) 6.64(114) 55 6.73 (75) <4.7 (17) <4.7 (0) 5.87 (69) 56 7.19 (108) <4.7 (4)<4.7 (8) 5.87 (46) 57 7.03 (93) <4.7 (5) <4.7 (8) 6.38 (82) 63 7.16(107) <4.7 (5) <4.7 (5) 6.19 (89) 64 6.97 (104) <4.7 (5) <4.7 (9) 5.49(81) 65 7.50 (104) <4.7 (7) <4.7 (11) 6.65 (97) 66 6.56 (94) <4.7 (12)<4.7 (0) 5.61 (66) 67 6.90 (114) <4.7 (48) <4.7 (4) 6.30 (104) 68 6.09(94) NT NT 5.43 (64) 69 7.98 (120) <4.7 (12) <4.7 (14) 6.62 (78) 70 6.57(107) <4.7 (5) <4.7 (3) 6.10 (55) 74 7.28 (132) <4.7 (19) <4.7 (4) 6.55(97) 75 7.06 (102) <4.7 (14) <4.7 (13) 6.10 (87) 78 7.37 (115) <4.7 (5)<4.7 (0) 6.38 (51) 79 7.01 (113) <4.7 (7) <4.7 (27) 6.06 (27) 80 7.43(89) <4.7 (15) <4.7 (7) 6.28 (71) 81 6.85 (110) <4.7 (0) <4.7 (7) <4.7(9) 82 7.26 (89) <4.7 (16) <4.7 (2) 5.79 (81) NT—Not tested

Example B

Passive Avoidance

Studies were carried out as described previously by Foley et al., (2004)Neuropsychopharmacology. In the passive avoidance task scopolamineadministration (1 mg/kg, i.p.) at 6 hours following training renderedanimals amnesic of the paradigm. A dose range of 3, 10, and 30 mg/kg(po) free base, administered 90 minutes prior to the training period viaoral gavage, was examined.

Example 27 was found to reverse scopolamine-induced amnesia of theparadigm in a dose-dependent manner, with an approximate ED₅₀ of ca. 10mg/kg (po). The effect of 30 mg/kg was similar to that produced by thecholinesterase inhibitor donepezil (0.1 mg/kg, ip) which served as apositive control (FIG. 1).

Example 65 was found to reverse scopolamine-induced amnesia of theparadigm in a dose-dependent manner, with significant effects observedafter acute administration of 10 and 30 mg/kg (p<0.05; Bonferroni posthoc test). The effect at 10 and 30 mg/kg was not significantly differentto that produced by the cholinesterase inhibitor donepezil (0.1 mg/kg,i.p.), which served as a positive control (FIG. 2).

Example 65 was found to reverse scopolamine-induced amnesia in adose-dependent manner, with significant effects observed after acuteadministration of 10 mg/kg (po) (p<0.05; Bonferroni post hoc test). Theeffect at 10 mg/kg was not significantly different to that produced bythe cholinesterase inhibitor donepezil (0.1 mg/kg, i.p.), which servedas a positive control. Combination of Example 65 and donepezil did notresult in a loss of activity, rather the combination had an additiveeffect at each dose combination as analysed by Mann Whitney u-test (FIG.3).

Example C

Irwin Profile

The method, which detects the principal effects of a test substance onbehaviour and physiological function, follows that described by Irwin(1968) Psychopharmacologia. Cholinergic side effects are potentiallyvisible in the behavioural readout of the Irwin assay, and an absence ofthese side effects can be taken as an indication that agonism of the M2and M3 receptors is not significant in vivo.

Rats are administered the test substance or its vehicle, and areobserved in simultaneous comparison with a control group. Behaviouralmodifications, physiological and neurotoxicity symptoms, rectaltemperature and pupil diameter are recorded according to a standardizedobservation grid derived from that of Irwin. The grid contains thefollowing items: death, convulsions, tremor, Straub tail, alteredactivity, jumping, abnormal gait (rolling, tiptoe), motorincoordination, altered abdominal muscle tone, loss of grasping,akinesia, catalepsy, loss of traction, loss of balance, fore-pawtreading, writhing, piloerection, stereotypies (sniffing, chewing, headmovements), head-twitches, scratching, altered respiration, aggression,altered fear/startle, altered reactivity to touch, ptosis, exophthalmia,loss of righting reflex, loss of corneal reflex, analgesia,defecation/diarrhea, salivation, lacrimation, rectal temperature(hypothermia/hyperthermia) and pupil diameter (myosis/mydriasis).Observations were performed at 15, 30, 60, 120, 180 minutes and 24 hoursafter administration of Example 27. No effects on any parameter wereobserved at any time point at doses of 3, 10, 30 and 75 mg/kg (po) whencompared to vehicle control.

Observations were performed 15, 30, 60, 120, and 180 minutes postadministration of Example 65. No significant effects on any parameterwere observed at these time points at doses of 5, 10, 20 and 40 mg/kgwhen compared to vehicle control.

Example D

Novel Object Recognition

The novel object recognition paradigm is based on the greaterspontaneous exploration of a novel object, compared with a familiarobject, shown by rodents (Ennaceur and Delacour, 1988). The paradigm isconsidered a model of working memory and does not involve primaryreinforcement such as food reward or noxious stimulus, thus making itanalogous to memory tests employed in human clinical trials. Male Wistarrats were assessed for cognitive ability in a test apparatus comprisingan open-field arena placed in a sound-attenuated room under dimmedlighting. Images of the open-field were captured by digital camera, andviewed on a monitor in an adjoining room. Each rat was subjected to theprocedure separately and care taken to remove any olfactory/taste cuesby cleaning the arena and test objects with alcohol between trials andrats. All tests are video scored blind to treatment. Following a10-minute habituation period, each rat was placed into the test arena inthe presence of two identical objects (plastic shapes). Each rat wasplaced facing the same direction at the same position in the arena, andthe time spent actively exploring the objects during a 5-minute trainingperiod (T1) was recorded. The rat is returned to its home cage betweentests. After 24 hours, each rat was again placed in the test arena for 5minutes (T2) in the presence of one of the familiar objects and a novelobject, and the time spent exploring both objects again recorded. Thepresentation order and position of the objects (left/right) wasrandom/zed between rats to prevent bias from order or place preference.Doses of 3, 10 or 30 mg/kg of test compound were administered by oralgavage 90 minutes prior to training (n=8). Donepezil (0.1 mg/kg) andgalanthamine (3 mg/kg) were administered via intraperitoneal injection60 minutes prior to training. Vehicle-treated controls were employed forcomparison.

Statistical analysis determined that treatment with 10 and 30 mg/kg forExample 65 and 3 mg/kg of the positive control galanthaminesignificantly improved novel object recognition memory when compared tovehicle-treated controls (p<0.05) (FIG. 4). Donepezil (0.1 mg/kg) waswithout effect on novel object recognition. During the 10 minutetraining period in the apparatus, animals were scored for exploratorybehaviour. There was no difference as regards exploration for eitherobject or between vehicle-treated controls and any drug treatment group.

Example E

CA1 Cell Firing

Rat hippocampal slices of 400 μm thickness were cut in chilled (<4° C.)artificial cerebrospinal fluid (aCSF, composition in mM: NaCl 127, KCl1.6, KH₂PO₄ 1.24, MgSO₄ 1.3, CaCl₂ 2.4, NaHCO₃ 26 and D-glucose 10)using vibratome Slices were maintained in oxygenated (95% O₂/5% CO₂)aCSF at room temperature for at least 1 hr prior to electrophysiologicalrecording, after which they were transferred to an interface chamber andconstantly perfused with warmed (30° C.) oxygenated aCSF at a flow rateof 1.5-3 ml·min-1. Schaffer collaterals were then stimulated (1-20 V,0.1 ms pulse width, 0.033 Hz) with a concentric bipolar electrode toevoke field excitatory post synaptic potentials (fEPSPs) recorded fromthe stratum radiatum of the CA1 region. Experiments were performed toexamine the effect of compound compared to 1 μM carbachol (CCh), on theamplitude of fEPSPs in the CA1 region of rat hippocampal slices. 1 μMCCh was initially applied until steady-state, followed by wash, beforeperforming a five point cumulative concentration-response to compound,Each compound was tested on 6 slices and results averaged. Drugpreparation; compound was dissolved in 100% DMSO at a stockconcentration of 30 mM, and diluted according to requirements,carbamoylcholine chloride (CCh) was purchased from Sigma (Cat #C4382)and dissolved at a stock concentration of 1 mM in ddH₂O.

TABLE 4 Ex. No. Cell Firing EC50 (mM) 6 4.10E−06 ± 0.2  27 1.21E−06 ±0.08 40 9.40E−06 ± 0.09 65 2.05E−06 ± 0.06

Example F

Pharmaceutical Formulations

(i) Tablet Formulation

A tablet composition containing a compound of the formula (1) isprepared by mixing 50 mg of the compound with 197 mg of lactose (BP) asdiluent, and 3 mg magnesium stearate as a lubricant and compressing toform a tablet in known manner.

(ii) Capsule Formulation

A capsule formulation is prepared by mixing 100 mg of a compound of theformula (1) with 100 mg lactose and optionally 1% by weight of magnesiumstearate and filling the resulting mixture into standard opaque hardgelatin capsules.

EQUIVALENTS

The foregoing examples are presented for the purpose of illustrating theinvention and should not be construed as imposing any limitation on thescope of the invention. It will readily be apparent that numerousmodifications and alterations may be made to the specific embodiments ofthe invention described above and illustrated in the examples withoutdeparting from the principles underlying the invention. All suchmodifications and alterations are intended to be embraced by thisapplication.

1-20. (canceled)
 21. A compound:

or a salt thereof.
 22. A pharmaceutically acceptable salt of thecompound according to claim
 21. 23. An acid addition salt of thecompound according to claim
 21. 24. The acid addition salt according toclaim 23, wherein the acid is selected from the group consisting ofacetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric,ethane-1,2-disulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, formic,fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic(e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric,glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric,hydriodic), isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic),lactobionic, acetyl leucine, maleic, malic, (−)-L-malic, malonic,(±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic,naphthalene-1,5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic,L-pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulfuric, tannic, (+)-L-tartaric, (−)-D-tartaric,(−)-dibenzoyltartaric, thiocyanic, p-toluenesulfonic, undecylenic andvaleric acids, as well as acylated amino acids and cation exchangeresins.
 25. A pharmaceutical composition comprising a compound accordingto claim 21 and a pharmaceutically acceptable excipient.
 26. Apharmaceutical composition comprising a pharmaceutically acceptable saltaccording to claim 22 and a pharmaceutically acceptable excipient.
 27. Apharmaceutical composition comprising an acid addition salt according toclaim 23 and a pharmaceutically acceptable excipient.
 28. Apharmaceutical composition comprising an acid addition salt according toclaim 24 and a pharmaceutically acceptable excipient.
 29. A method oftreating Alzheimer's disease, dementia with Lewy bodies orschizophrenia, comprising administering an effective amount of thecompound according to claim 21 to a patient in need thereof.
 30. Themethod according to claim 29, wherein the disorder is Alzheimer'sdisease.
 31. The method according to claim 29, wherein the disorder isdementia with Lewy bodies.
 32. The method according to claim 29, whereinthe disorder is schizophrenia.